University of Virginia Health System

Potential Research Projects for Medicine Residents

Residents should contact the faculty members associated with a project of interest.

Immune and Cellular Mechanisms of Interleukin-4 Antagonism
Contact: Larry Borish

These studies are focused on identifying immune mechanisms of IL-4 antagonism. Our hypothesis is that IL-4 antagonism will inhibit Th2-like lymphocyte differentiation, activity, and survival. Our studies demonstrate dramatic inhibition of established effector T lymphocytes. IL-4 inhibition reduces production of cytokines associated with Th2-like cells (IL-5 and IL-13) while having no influence on the Th1 cytokine IFN-?. IL-4 antagonism is also associated with dramatic upregulation of IL-10 production. This reflects activation of mononuclear phagocytic cells but in the allergic airway may also be derived from differentiation of NK T cells into an IL-10-producing pathway.

Molecular Genetic Studies in Allergic Disease and Asthma
Contact: Larry Borish

My laboratory has described polymorphisms in the interleukin (IL)-4, IL-9, IL-10, and transforming growth factor (TGF)-ß1 promoters that link in several population studies to the presence of immune disorders including neoplasia, autoimmune disease, allergies and asthma. The IL-10 promoter polymorphism is located between sp1/sp3 and putative ets sites and influences both promoter strength and avidity of sp1/sp3 complexes. IL-9 has many biological activities that support its having an important role in the pathophysiology of asthma and allergy including the ability of IL-9 to induce IgE, IL-5, and leukotriene receptors and promotion of Th2 lymphocyte, mast cell, and eosinophil function. The IL-9 promoter polymorphism represents an A/G base exchange at -351 base pairs from the open reading frame and is associated with increased binding by nuclear transcription factors to an NF-?B site.

Immune Mechanisms in Chronic Hyperplastic Eosinophilic Sinusitis (CHES) and Aspirin- Exacerbated Respiratory Disease
Contact: Larry Borish

We are investigating the role of cysteinyl leukotrienes in chronic hyperplastic eosinophilic sinusitis and, in particular, how this pertains to the development of aspirin intolerance. We hypothesize that cysteinyl leukotrienes and other arachidonate metabolites acting through eosinophil activation, promote fibroblast proliferation, secretion of proinflammatory cytokines, and the aggressive remodeling characteristic of CHES and polyp formation. Cysteinyl leukotriene concentrations were significantly higher in tissue obtained from subjects with CHES as compared to non-eosinophilic inflammatory sinusitis or healthy sinus tissue. 5-lipoxygenase (5-LO), 5-LO activating protein (FLAP) and leukotriene C4 synthase (LTC4S) were expressed in the majority of eosinophils and subsets of mast cells, monocytes and macrophages. 5-LO and FLAP, but not LTC4S, were also expressed in neutrophils, while conversely epithelial cells expressed LTC4S but not 5-LO or FLAP. A C-to-A promoter polymorphism in the LTC4S gene was associated with presence of CHES. CysLT1 receptors (both mRNA and protein) were expressed in the majority of eosinophils and in subsets of mast cells, monocytes, macrophages and neutrophils; CysLT2 receptors (mRNA and protein) were expressed in eosinophils, mast cells, and monocytes/macrophages. CysLT2 receptors are uniquely important in eosinophil activation and blockage of the type 1 receptor, has no influence on degranulation. Current studies emphasize the role of CysLT and other phospholipid metabolites including lysophatidic acid (LPA) and PgE2 in fibrotic pathways. We are also investigating the regulation and function of CysLT1 and CysLT2 receptors on immune cells including monocytes, T and B lymphocytes, and dendritic cells. These studies emphasize the importance of the CysLT synthetic and signaling pathway in the key pathological cells in CHES in aspirin-exacerbated respiratory disease and provide strong rationale for the therapeutic use of CysLT modifying agents in this disease.

Regulatory T Cells in Atopic Dermatitis
Contact: Judith A. Woodfolk

Coronary Artery Disease
Prediction of Major Adverse Cardiovascular Events by Age-Normalized
Carotid Intimal Medial Thickness
Contacts: Yasmine S. Ali, Karen E. Rembold, Brad Weaver, Mary Beth Wills, Steven Tatar, Carlos R. Ayers, Christopher M. Rembold

Abstract
Background: Increases in carotid intimal medial thickness (IMT), as measured by noninvasive ultrasonography, have been associated with increased risk of myocardial infarction and stroke, particularly in adults 65 years of age or older. We investigated the value of age-normalized carotid IMT measurements in predicting major adverse cardiovascular events in a population of patients referred for carotid IMT measurement.

Methods: Since 1995, 727 patients had carotid IMT measured at the University of Virginia's Preventive Cardiology practice.We successfully contacted 706 of these patients to determine clinical outcomes; 21 patients were lost to follow-up. The 706 patients were entered into a database, age-specific quartiles of carotid thickness developed, and odds ratios were calculated with logistic regression.

Results: Over a mean follow-up period of 4.78 years (range, 2.0-9.3 years), 20 patients had major adverse cardiovascular events: seven patients had myocardial infarctions; seven required revascularization; and six had a stroke or transient ischemic attack. The incidence of events directly correlated with age-normalized measurements of carotid bulb and internal carotid IMT. The highest quartile of carotid bulb IMT demonstrated an odds ratio for all events of 5.8 (95% confidence interval, 1.3-26.6; P = 0.023) when compared to the quartile with the lowest thickness (P = 0.007 for trend). A similar trend for quartiles of internal carotid IMT was also observed (P = 0.03). Common carotid IMT did not significantly predict events.

Conclusions: Age-normalized measurement of carotid bulb and internal carotid IMT may be helpful in determining which individuals would most benefit from aggressive risk-factor modification.

Electrophysiology, Atrial Fibrillation, and Imaging
Contact: John Ferguson, Ch.B., FACC, M.B., M.B. Ch.B. 

Dr. Ferguson's projects focus on disease processes that cause arrhythmia, evaluation of this pathology and the invasive and non-invasive treatments to cure arrhythmia. The primary focus is assessment of the underlying substrate and mechanisms of atrial fibrillation and the development of new techniques to treat this arrhythmia using catheter ablation. His clinical practice involves complex ablation procedures in the electrophysiology (EP) laboratory and consequently research projects revolve around these patients. He has helped develop 3-dimensional imaging of the left atrium and partnered with industry to evaluate the use of this technology in animal and subsequent clinical studies. He collaborates with cardiology imaging colleagues to assess left atrial function before and after treatment of atrial fibrillation with MRI, CT and echocardiographic scans. He has also developed and published on the novel use of technology, such as intracardiac ultrasound to facilitate EP ablation procedures.

Cardiovascular Magnetic Resonance Imaging from Mouse to Man
Contact: Christopher Kramer, M.D. 

Id3 in Vascular Disease
Contact: Coleen A. McNamara M.D.

Our laboratory is interested in the role of Id3 (a helix-loop-helix transcription regulator) in vascular disease. Our recent work with animal models demonstrates that Id3 plays a key role in the development of restenosis and atherosclerosis.  In addition, we have identified Id3-mediated gender differences and a role for Id3 in the accelerated vascular disease development in type 2 diabetes mellitus. We have identified several potential mechanisms and studies to elucidate these pathways are underway.

Techniques used in the laboratory to dissect out the cellular and molecular mechanisms whereby Id3 regulates vascular disease development include: animal models of restenosis and atherosclerosis, FACS, cell culture, Western blotting, transfection, RT-PCR, immunohistochemistry, cloning, site-directed mutagenesis, proliferation assays, apoptosis analysis, migration assays, two-hybrid analysis, bone marrow transplantation, immunoprecipitation, antibody generation, adenoviral gene delivery, microarray analysis, etc.

Detection of Atrial Fibrillation and Congestive Heart Failure in Patients with implanted Devices
Contact: Randall Moorman, M.D.

We are developing new algorithms for detection of AF and CHF in patients with pacemakers and ICDs. The goal is to present clinicians with AF burdens and CHF severity scores at the time of device interrogations. No AF burden information is present with current VVI devices, and no device reports CHF severity. Our algorithms perform well in the small number of public databases, and we are creating a large UVa database of Holter monitor results and CardioCare data. The techniques are those of database research and medical informatics, and as much or little mathematics as you like. In particular, we are interested in the interplay of clinical factors with heart rate time series characteristics, and clinical insights would be greatly appreciated.

Role of Carotid Intimal Medial Thickness (CIMT) Ultrasound in Primary Prevention of Cardiovascular Disease
Contact: Chris Rembold, M.D.

CIMT determines the amount of atherosclerosis present in a person, allowing more accurate antidyslipidemic therapy. For example, it may show that despite an LDL of 150, there is little atherosclerosis and no need for treatment. Alternatively, in a person with a family history of CAD and an LDL of 110, it may show thickening and plaques suggesting a need to treat. It can be viewed as the "mammogram of the heart". Since 1995, we have measured CIMT in about 1300 patients. In 2003, a prior resident, Yasmine Ali, did a 5 year followup study on our patients and found that CIMT thickening in the highest quartile predicted a 6 fold increase risk for a MI, CVA, or need for revascularization. This work is published in Atherosclerosis 187:186-190, 2006.

I see two potential resident projects: (a) We could do a 10 year followup on our patients and see in CIMT still predict (or better predicts) death, MI, CVA, and/or need for revascularization. (b) We could look at the prediction of death, MI, CVA, and or need for revascularization based on plaque characteristics (calcified, echolucent, protuberant, etc.).

Diagnosis of Sleep Apnea by Characteristics of Snoring Sounds
Contact: Chris Rembold, M.D.

In a collaboration with Dr. Paul Suratt in Pulmonary, we found that the spectral characteristics of snoring sounds can predict sleep apnea in children (Sleep 27:1154, 2004 and J Applied Physiology 98:1755, 2005). We recorded the snoring sounds from 50 adults who had a sleep study. I see that a resident could analyze these data to see if the spectral characteristics of sleep sounds can predict adult sleep apnea.

Angiogenesis in Peripheral Vascular Disease
Contact: Amy Tucker, M.D.

Smooth Muscle Physiology
Contact: Brian R. Wamhoff, Ph.D., 434-243-6525 wamhoff@virginia.edu
Lab Manager: Pamela Schoppee-Bortz, Ph.D.

The overall focus of the Wamhoff lab is to understand the mechanisms that regulate smooth muscle cell (SMC) phenotypic modulation in health and disease. The vascular SMC plays a critical role in maintaining vessel tone but is also intimately involved in repairing injured vessels in response to atherogenic stimuli (bioactive lipids) or direct mechanical injury (stenting and angioplasty).

Our specific laboratory research interests include: 1) Atherosclerosis and Restenosis; 2) Excitation Transcription Coupling in SMCs and 3) Biomimetic Models of Vascular Disease. Our lab uses an integrated approach to study mechanisms of SMC phenotypic modulation from the in vitro molecular cell level to novel in vivo animal models of vascular disease. The CIT Master's candidate will use this paradigm to address the role of calcium signaling or bioactive phospholipids in regulating SMC phenotypic modulation in health and disease.

The candidate will learn the following: 1) How to formulate hypothesis driven/mechanistic research, 2) Fundamental molecular and cellular biology techniques that can be applied in any field of research, 3) Translational research from bench discoveries to novel animal models of atherosclerosis and vascular injury, 4) Manuscript preparation and essential grant writing skills for future endeavors. All of the reagents and animal models are available, including novel Cre/lox systems for smooth muscle selective gene deletion in vivo. It is expected that this research will result in the publication of a high quality manuscript and presentation of data at national meetings, e.g. AHA Scientific Sessions and/or ATVB Scientific Sessions. All projects are funded by the NIH, AHA or Pfizer.

Click here for more details of ongoing research projects.

Immunology, Molecular Biology and Genetics
Contact: Michael Brown, Ph.D.

A central objective of current research in the laboratory is aimed to examine, identify and characterize molecular and cellular mechanisms of innate immunity and antiviral host defenses. Classical genetics strategies are a mainstay for the research program as genetic diversity in common laboratory strains of mice clearly affects innate immune responses toward viruses and consequently may also contribute to variation in host disease resistance or susceptibility traits. Identification of major alleles, sculpted through natural selection (genetic diversity), that affect innate immune control (resistance alleles), a lack of immune control (susceptibility alleles), or altered or even dysfunctional immune control (potential autoimmune disease alleles), will undoubtedly foster our understanding of the immune system and should also lead to new potential targets for therapeutic interventions.

Two major research project areas established in the lab are:

1. Virus Immunity Research Microbiology, Immunology and Infectious Disease:
Natural killer cells are needed in the body to prevent and control malignancy and virus infection. In fact, NK cells in humans and mice have a major role in controlling virus infections. Our lab has shown that NK cells in C57BL/6 mice use a cell-surface activation receptor, referred to as Ly49H, to recognize and control murine cytomegalovirus (MCMV) infection. We have also shown in another strain of mice that the MHC controls NK cell-mediated virus immunity. We have been working toward the identification of the responsible MHC gene so that we can better understand how NK cells recognize and then respond to infected cells. Because human NK cells also use membrane-bound receptors for MHC class I molecules and may be important for controlling disease progression in HCV or HIV virus infected patients, our studies might also yield important insights into the role of human NK cells in virus infections.

2. Viral Pathogenesis Research Immunity and Inflammation:
We have shown that immune competent systemic lupus erythematosus (SLE-) prone NZM2328 mice display marked sialadenitis during acute MCMV infection when virus levels are elevated (d.14-28) in the salivary glands. Later, when viral latency is established in most MCMV-infected NZM2328 females (typically by d. 56 after infection), a qualitative shift from diffuse to focal inflammation in salivary and lacrimal glands occurs that is marked by lymphocyte aggregation in periductal foci, some with lymphocytes segregated into lymphoid-like structures. Additionally, we have shown that salivary gland function is also significantly compromised in NZM2328 mice at discrete times after infection. Interestingly, these features are similar to those observed in Sjögren's Syndrome (SS) patients who display exocrine gland dysfunction. Thus, virus-induced sialadenitis in NZM2328 mice might prove useful in modeling SS or SS secondary to HCV infection. To extend our work and to investigate a potential role for genetic factors in virus-induced exocrinopathy, similar studies are underway in genetically-related inbred strains of mice. Future research is therefore aimed to investigate the genetic and cellular basis for virus-induced inflammation and exocrine gland dysfunction in this model system.

Pathogenesis of Autoimmune Diseases
Contact: Umesh S. Deshmukh, Ph.D.

My laboratory is interested in investigating the pathogenesis of systemic autoimmune diseases, particularly Systemic lupus Erythematosus (SLE) and Sjögren's syndrome (SS).

SLE is a complex autoimmune disorder with multiple organ involvement. Immune-complex mediated renal injury is one of the major complications of SLE. In my laboratory we are interested in identifying mechanisms responsible for the generation and sustenance of autoantibodies reactive against different lupus-associated antigens. We have established experimental mouse model systems of autoantibody generation and amplification within the Sm antigens. Immune response to Sm proteins is a hallmark of SLE. Currently we are in the process of identifying genetic regions that contribute towards the amplification of autoantibody responses to Sm proteins. We are also testing different therapeutic measures to intervene in these processes.

Sjögren's syndrome (SS) is a chronic autoimmune disorder characterized by lymphocytic infiltration in the salivary glands. Xerostomia or dry mouth is a major complication of SS. We have established experimental mouse model systems that mimic the human disease. In one model system, treatment of mice with a Toll-like receptor 3 ligand poly(I:C), rapidly induces salivary gland dysfunction. Our preliminary studies indicate that localized inflammatory cytokine production is mainly responsible for the glandular dysfunction. Currently we are investigating the mechanisms for this dysfunction and novel therapeutic interventions to reverse the course of disease.

Recent Publications Relevant for SLE and SS:
1. Deshmukh US, H Bagavant, D Sim, V Pidiyar, and SM Fu. 2007. A SmD Peptide Induces Better Antibody Responses to Other Proteins within the Small Nuclear Ribonucleoprotein Complex than to SmD Protein via Intermolecular Epitope Spreading. J. Immunol. 178:2565-2571.
2. Deshmukh US, Y Ohyama, H Bagavant, F Gaskin, and SM Fu. 2008. Inflammatory stimuli accelerate sjogren's syndrome-like disease in NZB/W F1 mice. Arthritis and Rheumatism, 58:1318-1323.
3. Deshmukh US, SR Nandula, PR Thimmalapura, YM Scindia and H Bagavant. 2008. Activation of innate immune responses through toll-like receptor 3 causes a rapid loss of salivary gland function. J Oral Pathol Med, in press.
4. Scindia YM, US Deshmukh, PR Thimmalapura and H Bagavant. 2008. Anti-alpha 8 integrin immunoliposomes: A novel system for delivery of therapeutic agents to the renal glomerulus in systemic lupus erythematosus. 2008. Arthritis and Rheumatism, in press.

Genetic and Cellular Control of Multi-Organ Inflammation
Organ Development and Hormone Control of Organ-Specific Inflammation
Contact: Shyr-Te Ju, Ph.D.

We have three areas of basic science research:

1. We are studying autoimmune inflammation controlled by the CD4+CD25+Foxp3+ regulatory T cells (Treg). Mice genetically deficient in Treg including Il2-/-, Il2r?-/- and Foxp3sf/Y (Sf) are used. The Sf mice in particular are totally devoid of Treg and display the X-linked IPEX (Immune dysregulation, Poly-endocrinopathy, Enteropathy, X-linked) syndrome characteristics of patients bearing mutations in the Foxp3 gene. Sf mice die at 4 weeks after birth with severe multi-organ inflammation. Inflamed organs include skin, ear, tail, lung, liver, and kidney. However, many organs/tissues are spared from the attack. Interestingly, Sf mice contain dormant T cells capable of transferring new diseases such as sialoadenitis, dacryoadenitis, pancreatitis, gastritis, intestinal inflammation, colitis, and myositis in Rag1-/- recipients. Moreover, transfer of the multiple organ diseases could be suppressed by Treg. Our study shows a large repertoire of lymphocytes against various organs/tissues in Sf mice as well as Treg in B6 mice capable of suppressing the expansion of these lymphocytes. My goal for the next few years is to characterize the pathogenic T cell and Treg repertoires with respect to their organ/antigen specificity.

Mutation of the Foxp3 in Sf mice results in severe multi-organ inflammation, and early death at 4 weeks old. However, Sf mice simultaneously bearing the Il2-/- (Sf.Il2-/-) or Faslpr/lpr gene (Sf.Faslpr/lpr) have extended lifespan despite totally lacking Treg, indicating a role of IL-2 and CD95 (Fas) signaling pathways in the multi-organ inflammation beyond the Treg checkpoint. Importantly, the pattern of organ-specific inflammatory response of Sf.Il2-/- mice resembled Il2-/- mice whereas that of Sf.Faslpr/lpr was similar to Sf mice, indicating that the distinct and weakened manifestation in Il2-/- mice was not caused by the residual Treg and that both Il2-/- and Faslpr/lpr genes prolong the lifespan of Sf mice but by different mechanisms. One of our goals is to understand how IL-2 regulates systemic inflammation in an organ-specific manner.

2. CD103 (?E?7) is an integrin family member implicated in cutaneous and mucosal inflammatory response. CD103 expression on T cells of Il2-/- and Sf.Il2-/- mice was greatly reduced as compared with B6 and Sf mice. The defect in CD103 expression could explain why the inflammation in the skin, tail, and lung of Sf.Il2-/- mice was significantly reduced as compared with Sf mice. Previous study has shown that TGF?1 is important for CD103 expression. Our preliminary study suggests that the co-presence of IL-2 and TGF?1 is required for the optimal expression of CD103. Regulation of CD103 expression and how CD103-dependent cell trafficking affects multi-organ inflammation are under investigation.

3. Il2-/- or Il2r?-/- mice invariably develop inflammation in the submandibular gland (SMG) and salivation dysfunction, a disease resemble Sjögren's syndrome. In contrast, the SMG of Sf mice were not inflamed. Moreover, Sf mice co-expressing Faslpr/lpr, Il2-/- or Il2r?-/- gene remained free of inflammation in their SMG even though they lived significantly longer and contained T cells capable of inducing inflammation in the SMG of Rag1-/- recipients. The SMG of Foxp3sf/Y mice was growth arrested before the stage when dominant sexual-dimorphic display of granular convoluted tubules (GCT) normally occurred, yet testosterone treatment restored GCT development but not inflammation. These observations indicate that Foxp3sf/Y inhibits SMG development and define a critical development stage that renders SMG resistance to inflammation induced by competent T cells. We hypothesize that the expression of a critical antigen(s) (not associated with GCT development) is inhibited in Sf mice. One of the goals in this project is to identify the antigen(s) and define the specificity of the pathogenic T cells.

Laboratory Techniques: Genotyping, PCR, Flow Cytometry, Cell Purification, Cell Sorting, Adoptive Transfer, Histology, and general techniques of biochemistry, cell biology, and molecular biology.

Publications of the last three years:

1. Sharma R, Bagavant H, Jarjour WN, Sung S-s, and Ju S-T. The Role of Fas in the Immune System Biology of IL-2R? Knockout Mice: Interplay among regulatory T cells, inflammation, hemopoiesis and apoptosis. J. Immunol. 2005. 175: 1965-1973.
2. Sharma R, Zheng L, Guo X, Fu SM, Ju S-T*, and Jarjour WN. Novel animal models for Sjögren's syndrome: transfer of salivary gland dysfunction from regulatory T cell-deficient mice. J. Autoimmunity. 2006: 27: 289-296. (*co-senior author contribute equally)
3. Sharma R, Zheng L, Deshmukh US, Jarjour WN, Sung S-s, Fu SM, and Ju S-T. Cutting Edge: A regulatory T cell-dependent novel function of CD25 (IL-2R?) controlling memory CD8+ T cell homeostais. J. Immunol. 2007. 178: 1251-1255.
4. Sharma R, Jarjour WN, Zheng L, Gaskin F, Fu SM, and Ju, S-T. Large functional repertoire of regulatory T-cell suppressible autoimmune T cells in scurfy mice. J. Autoimmunity. 2007. 29: 10-19.
5. Zheng L, Sharma R, Gaskin F, Fu SM, and Ju S-T. A novel role of IL-2 in organ-specific autoimmune inflammation beyond regulatory T-cell checkpoint: Both IL-2 knockout and Fas mutation prolong lifespan of scurfy mice but by different mechanisms. J. Immunol. 2007. 179: 8035-8041.
6. Zheng L, Sharma R, Kung JT, Deshmukh US, Jarjour WN, Fu SM, and Ju S-T. Pervasive and stochastic changes in the TCR repertoire of regulatory T cell-deficient mice. Int. Immunol. 2008. 20: 517-523.

Interleukin-2 and Regulatory T Cells in Autoimmune Inflammatory Disorders
Contact: Rahul Sharma, Ph.D.

1. Interleukin-2 signaling in effector T cell responses during inflammation:
Regulatory T cells (Treg) exert the major mechanism of peripheral tolerance and their deficiency causes early mortality in mice and humans due to multi-organ auto-immune syndrome. In collaboration with Dr. Shyr Te-Ju, we study the interplay of Treg and auto-reactive T cells, in terms of their homeostasis, effector function and migration/homing to the sites of inflammation. We have shown that IL-2 signaling plays an important role in all of these processes. For our studies, we use mice which are deficient in Interleukin-2 signaling or the mice deficient in Treg lineage transcription factor Foxp3. We have demonstrated that IL-2 signaling acts as a modifier of the organ specificity of the auto-immune response and blocking this pathways leads to prolongation of lifespan. The project focuses on how IL-2 signaling impacts the expression of different homing receptors on T cells to modify the disease phenotype.

2. Regulatory T cell deficiency in Sjogren's syndrome like disorder:
We also study Sjogren's syndrome - a debilitating autoimmune disease of the exocrine glands. This is a systemic disease primarily affecting salivary and lacrimal (lachrymal) glands, resulting in Xerostomia (dry mouth) and Keratoconjunctivitis sicca (dry eyes). Other manifestations include lung, liver, kidneys, vasculature, skin and reproductive organs. We have shown that Treg deficiency is one of the underlying factors for Sjogren's syndrome and that in murine models systemic inflammation can cause arrest in the development of sub-mandibular glands. The project focuses on the implications of systemic auto-immunity on the development and function of salivary glands and other exocrine organs.

Laboratory methods: Extensive mice breeding to generate mice with multiple mutations, histological analysis, flow cytometry, standard molecular biology, cellular immunology, adoptive transfer studies and whole animal studies.

Selected Publications:
1. Zheng L*, Sharma R*, Gaskin F, Fu SM*, Ju ST*. A novel role of IL-2 in organ-specific autoimmune inflammation beyond regulatory T cell checkpoint: both IL-2 knockout and Fas mutation prolong lifespan of Scurfy mice but by different mechanisms. J Immunol. 2007 Dec 15;179(12):8035-41. *equal contribution.
2. Sharma R, Jarjour WN, Zheng L, Gaskin F, Fu SM, Ju ST. Large functional repertoire of regulatory T-cell suppressible autoimmune T cells in scurfy mice. J Autoimmun. 2007 Aug;29(1):10-9.
3. Sharma R, Zheng L, Deshmukh US, Jarjour WN, Sung SS, Fu SM, Ju ST. A regulatory T cell-dependent novel function of CD25 (IL-2Ralpha) controlling memory CD8(+) T cell homeostasis. Cutting Edge - J Immunol. 2007 Feb 1;178(3):1251-5.
4. Sharma R, Zheng L, Guo X, Fu SM, Ju ST, Jarjour WN. Novel animal models for Sjögren's syndrome: expression and transfer of salivary gland dysfunction from regulatory T cell-deficient mice. J Autoimmun. 2006 Dec;27(4):289-96.
5. Sharma R, Bagavant H, Jarjour WN, Sung SS, Ju ST. The role of Fas in the immune system biology of IL-2R alpha knockout mice: interplay among regulatory T cells, inflammation, hemopoiesis, and apoptosis. J Immunol. 2005 Aug 1;175(3):1965-73.

Dendritic Cells
Contact: Sun-sang J. Sung, Ph.D.

1. Dendritic cells in allergic airway inflammation and hyperresponsiveness:
Dendritic cell functions are critical in antigen-specific T cell responses in the lung. We have characterized lung dendritic cell populations and obtained gene expression information on both resting and activated dendritic cell subsets by microarrays. The data showed that the expression patterns of the subsets are quite distinct, and provide candidate genes responsible for the immune function of dendritic cell subsets in lung inflammation. The next phase of the work is to go into detail and study the gene expression of dendritic cells related to the mechanism of antigen presentation, migration, and effector functions of dendritic cells.

2. Dendritic cells in food allergy:
Food allergy is a significant public health problem and the etiology of the disease is unclear. We have focused on the function of dendritic cells and regulatory T cells in food allergy. The questions to address are: (1) which subset of intestinal dendritic cell is responsible for the allergic reactions to allergy; and (2) what is the role of regulatory T cells in intestinal allergenic responses; and (3) can we alleviate food allergy responses by the infusion of antigen-specific regulatory T cells. We will use various mutant mice to address the issue of the involvement of different dendritic cell subsets in food allergen responses and to generate antigen-specific regulatory T cells.

3. Dendritic cells in airway antigenic tolerance:
Animals have been shown to develop a nonresponsive state called tolerance in response to food or airway antigens. The mechanism for this toleragenic state has not been elucidated. We hypothesize that Foxp3+ T cells are responsible for this antigen-specific, systemic, and long-lasting nonresponsive state and that certain lung or gut dendritic cell subsets are responsible for inducing or stimulating these Foxp3+ regulatory T cells in response to airway or gut antigen delivery. An immunization scheme has been developed to induce the toleragenic state and will be use to identify the dendritic cells involved in this tolerance induction and the factors involved in the regulatory T cell-mediated toleragenic state. Mutant mice will be used extensively in these studies.

References:
1. Sung, S., C. E. Rose, and S. M. Fu. 2001. Intratracheal priming with ovalbumin- and ovalbumin 323-339 peptide- pulsed dendritic cells induces airway hyperresponsiveness, lung eosinophilia, goblet cell hyperplasia, and inflammation. J Immunol 166:1261-1271.
2. Sung, S.-S. J., S. M. Fu, C. E. Rose, Jr., F. Gaskin, S.-T. Ju, and S. R. Beaty. 2006. A Major Lung CD103 ({alpha}E)-beta7 Integrin-Positive Epithelial Dendritic Cell Population Expressing Langerin and Tight Junction Proteins. J Immunol 176:2161-2172.
3. Sung, S.-s. J., J. A. Lannigan, and C. E. Rose, Jr. 2007. Lung eosinophils homing in homeostasis. J Immunol 178:S192-a-.

AM & Cyr61 in Breast and Prostrate Cancer
Contacts: John Chirgwin, Ph.D. in collaboration with Theresa Guise, M.D.

Roles of adrenomedullin (AM) and cysteine-rich protein 61 (Cyr61) in breast and prostate cancer bone metastases and progression to chemoresistance. AM and Cyr61 are secreted proteins that stimulate tumor growth and angiogenesis. They also stimulate bone cell proliferation and are highly expressed by aggressively metastatic breast and prostate cancer cells.  We found that mRNAs for both factors are induced by the anti-estrogen tamoxifen in less aggressive ER+ breast cancers. The two factors may thus contribute to bone metastases and resistance to anti-estrogens. We are developing models to test the importance of AM and Cyr61 in cancer in animal models, using human cancer cell lines with AM and Cyr61 expression increased with stable lentiviral expression or knocked down by siRNAs. Experiments involve determining control of AM and Cyr61 gene expression (assayed by PCR and Western blotting) by BRCA1, Rho signaling and the hypoxic response pathway. Small molecule antagonists of hypoxia and the AM receptor are being tested.
Website: http://www.aurbachlabs.org/

Role of Prostate PSA in Osteoblastic Metastasis
Contacts: John Chirgwin, Ph.D. in collaboration with Theresa Guise, M.D.

Parathyroid hormone-related protein (PTHrP) is made by prostate cancers and stimulates osteolytic bone destruction. However, PSA protease cleaves PTHrP into a 23 amino acid fragment that stimulates osteoblastic new bone formation, which is characteristic of prostate bone metastases. We are developing an animal model to test the physiological significance of PTHrP cleavage by PSA. The experiments involve detailed analysis of bone metastases in mice bearing PSA+/PTHrP+ prostate cancer metastases and treated with inhibitors. We are also investigating the receptor signaling stimulated by the peptide fragment and the role of the Wnt and integrin signaling pathway. Methods involve treating cells in culture with PTHrP 1-23 and assessing changes in gene expression by RT-PCR and Western blotting, in particular of the Wnt-signaling inhibitor Dkk1 and the integrin ligand Cyr61, and assaying luciferase reporters responsive to activation of the corresponding signaling pathways.
Website: http://www.aurbachlabs.org/

Reproductive Biology / PCOS
Contact: Sue Moenter, Professor of Medicine and Cell Biology

Animal model of reproductive biology/PCOS. This is a great project but will require some lead time and a couple months of dedicated time for working with the animal model.

Clinical Approaches to Inflammatory Bowel Disease (Crohn's Disease and Ulcerative Colitis)
Contact: Steve Bickston, M.D.

The goal of the clinical inflammatory bowel disease clinical group is to advance the understanding of the causes, treatment and personal impact of inflammatory bowel diseases.  This is done in collaboration with basic scientists and outcomes researchers.  The inpatient DHC is a collaborative unit involving the DOM, other clinical departments, nutrition, and staff and is substrate for a wide variety of clinical projects.

Sample publications:

1. Behm BW, Bickston SJ. Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn's disease. Cochrane Database of Systematic Reviews 2008, Issue 1. 23 January 2008.
2. Procaccini N, Bickston SJ. Disability in the Inflammatory Bowel Diseases:  Impact of Awareness of the Americans with Disabilities Act. Pract Gastroenterol 31 (12) Dec 2007. (Residency research project)
3. Arseneau KO, Sultan S, Provenzale DT, Onken J, Bickston SJ, Foley E, Connors AF Jr, Cominelli F. Do Patient Preferences Influence Decisions on Treatment for Patients With Steroid-Refractory Ulcerative Colitis? Clin Gastroenterol Hepatol. 2006 July 7.
4. Brotman M, Allen JI, Bickston SJ, Campbell DR, Huddleston JM, Peterson LE, Schoenfeld PS, Sennett CS, Willis JR. AGA Task Force on Quality in Practice: a national overview and implications for GI practice. Gastroenterol. 2005 Jul;129(1):361-9.
5. Arseneau KO, Yeaton P, Kahaleh M, Cominelli F. Effect of digestive health care services integration on resource use and outcomes in patients with digestive disorders. Clin Gastroenterol Hepatol. 2003 Mar;1(2):145-51.

Interventional Endoscopy
Contact: Michel Kahaleh, M.D.

Dr. Kahaleh's research is focused on interventional endoscopy and the use of new devices to diagnose and treat biliary and pancreatic diseases. Using the adjunction of both Endoscopic Retrograde Cholangiopancreatography (ERCP) and Endoscopic Ultrasonography (EUS) has permitted successful treatment of pancreatic pseudocysts, and collection and performance of newly described procedures that have had a major impact on patient management. A major focus of his research is on understanding and preventing post-ERCP pancreatitis by investigating pharmaceutical agents and analyzing the efficacy of pancreatic stents. For the biliary aspect, he is actively analyzing the efficacy of metallic stents in both benign and malignant diseases.

Another area of investigation for Dr. Kahaleh is understanding and preventing biliary and pancreatic cancer. The objective of this area of research is to develop new diagnostic techniques for reducing the mortality associated with biliary and pancreatic cancers, by detecting them earlier and treating confirmed cancers using novel therapies such as laser therapy.

Advanced Gastrointestinal Endoscopy
Contact: Andrew Wang, M.D.

Dr. Wang's research centers on the use of endoscopic techniques and new technologies to diagnose and treat gastrointestinal diseases. Areas of active research and scientific interest include:

1. GI Neoplasia

• Use and efficacy of narrow-band imaging (NBI) to diagnose luminal and biliary neoplasia.
• Use and efficacy of endoscopic mucosal resection (EMR) in treating luminal GI neoplasia.
• Research into the applicability and efficacy of endoscopic submucosal dissection (ESD) in treating large dysplastic lesions and early cancers in the GI tract.

2. Pancreatico-biliary disease

3. GI Bleeding: Safety of using aspirin and/or clopidogrel in patients undergoing therapeutic GI endoscopy.

Diabetes Prevention Study
Contact: Joseph Aloi, M.D.

Currently involved in a diabetes prevention study using either lifestyle, valsartan, nateglinide, or both to prevent the development of Type 2 DM inpatients w/ IGT.

Additionally, current clinical trial w/ Vigdagliptin (DPP4 inhibitor) compared to rosiglitazone in newly diagnosed Type 2 DM.

Areas of ongoing observational research include the relationship of HDL lowering to improvement in Urinary Micro albumin excretion and the development of an office based paradigm for Zometa infusion for osteoporosis.

Opportunity exists and some limited funds available for clinical research in similar areas (DM, Osteoporosis) treatment and/or prevention.

Geriatric Prescribing
Contact: Kahlil Amir, M.D.

Education in Geriatric Care
Contact: Seki Balogun, M.D.

Professionalism
DVT Prophylaxis
Narrative Expression in Medicine
Contact: Daniel Becker, M.D.

Perform a Systematic Review of a Clinical Problem
Contacts: John Philbrick, M.D.; Daniel Becker, M.D.

The standard for clinical review papers has moved beyond a simple narrative review to the systematic review that uses principles of clinical epidemiology to evaluate and synthesize existing research to come to the best available answer to a clinical question.

This involves the following steps:
1. Identify a focused clinical question of interest to clinicians.
2. Develop a search strategy and perform a thorough search of the relevant literature to assemble pertinent articles.
3. Develop criteria to evaluate the methodologic strength of articles selected for review and review each article.
4. Develop an approach for summarizing and/or combining the results (meta-analysis) of reviewed articles.
5. Summarize/combine the results.
6. Develop clinical conclusions based on the results.
7. Write the manuscript.

End of Life Care
Contact: Leslie Blackhall, M.D.

Comparison of Clinical Documentation During Training
Contact: Steve Borowitz, M.D.

This project is still in planning. The basic premise is that the clinical chart does not effectively communicate clinical information but is a billing tool. We would like to take notes from the patient chart and have blinded reviewers evaluate that note for key clinical information. We would like to compare notes from different levels of training as well as evaluate what parts of the note exist for clinical reasons and what is there for billing reasons.

Use of Narrative Expression in Medicine
Contact: Julia Connelly, M.D.

Physical Exam and Diagnosis
Contact: Eugene Corbett, M.D.

Geriatric Care
Contact: Jonathan Evans, M.D.

Mindfulness Based Stress Reduction and Its Clinical Effects
Contact: Matthew Goodman, M.D.

Simulated Resuscitation in Training
Contacts: Brian Uthlaut, M.D.; George Hoke, M.D.; Tracy Hoke, M.D.

Using a clinical simulation lab in the Department of Surgery, we are looking at the use of simulators to train response and debriefing skills to the medicine code team. Our principle outcomes will be comfort with leadership roles, observed changes in behavior, and prevention of burnout.

Retinal Screening in Ddiabetes Using OPTOS scanner at UMA
Contact: John Leiner, M.D.

Issues in Patient Literacy and Medical Compliance
Contact: Jennifer Marks, M.D.

Education Regarding Chronic Pain Management
Narcotic Contracts
Physician-Patient Relationship in Addiction
Contact: Mary McMasters, M.D.

Chronic Illness Model and Care of Patients with Chronic Disease
Quality Improvement
Care of Indigent Patients
Contact: Mohan Nadkarni, M.D.

Medical Error, Quality Improvement
Contact: Margaret Plews-Ogan, M.D.

Ongoing projects include:

Ongoing Projects
Contact: Preston Reynolds, M.D.

Mindfulness Based Stress Reduction and Its Clinical Effects
Physician Wellness
Contact: John Shorling, M.D.

Recording and Analyzing Human Motion; Biokinetic Tracing
Contact: Mark Williams, M.D.

I am at the beginning phase of a very interesting research project that might be ideal for a medical resident as well as helpful to me. Briefly, I have a patent pending on a novel method of recording and analyzing human motion. The methodology has IRB approval. A consenting subject wears 4 or 5 ultra sensitive motion sensors (one on each extremity and one at the sacrum) and walks down a hall, turns around, and walks back. The waveforms generated by the sensors look similar to the waves on a 12 lead electrocardiogram.

My hypotheses relate to the capability of diagnosing various clinical entities based on the biokinetic tracing. I can handle up to three residents who would each work directly with me to collect the data on 10-20 patients with a known orthopedic or neurological condition such as severe hip or knee OA or s/p left MCA stroke or low pressure hydrocephalus. We will identify the biokinetic signature of the disorder and publish our findings in a peer reviewed journal. The entire project can be done in a few months and would make a significant contribution to our understanding of human motion.

Competency Based Education
Training Physicians in Systems-Based Thinking
Quality Improvement
Contact: John Voss, M.D.

Cancer Screening in Primary Care
Contact: Andrew Wolf, M.D.

Hospitalist Inpatient Initiatives
Contact: George Hoke, M.D.

Antriretroviral Levels in Patients with Diarrhea
Etiologies of Diarrhea in Haitian AIDS Patients
Contact: Rebecca Dillingham, M.D.

Project going on antiretroviral levels in patients with diarrhea needs data analysis. I also have some projects on etiologies of diarrhea in Haitian AIDS patients that need some PCR done.

AQ-R-Z To Repair Intestinal Injury
Contact: Richard Guerrant, M.D.

Building on our laboratory experience on enteric microbial toxins in pathogenesis and upon our clinical and field studies showing long-term developmental impact and ApoE genetic predispositions to protection from the cognitive impairment from diarrhea, the focus of our relevant laboratory work is on alanyl glutamine (AQ), arginine (R) and zinc (Zn) in repaving or repairing the damaged "tennis courts" of key absorptive intestinal function. Hence, we use tissue culture, organoid and in vivo (murine & rabbit) models of two leading enteric infections here and abroad: toxigenic C. difficile (the cause of antibiotic associated colitis worldwide) and Cryptosporidium (a leading protozoal cause of persistent diarrhea and growth failure). MSSRP projects would therefore focus on anti-inflammatory and tissue restitution effects of AQ, R, Zn or adenosine agonists in reversing C. difficile toxin or cryptosporidial damage of intestinal barrier/absorptive function.

As part of our reverse vaccinology collaboration with Dr. Greg Buck at VCU, we are conducting in vitro and in vivo assessments of C. parvum infections using HCT-8 cells and our malnourished mouse model. This work involves flow cytometry, in situ hybridization and quantitatve staining and PCR methods, and links to ongoing or potential clinical studies of these important enteric infections.

Galactose Polymers to Inhibit E. histolytica
Contact: William Petri, M.D.

Tracy Bercu worked in the lab in Charlottesville testing novel inhibitors of adherence of the protozoan parasite Entamoeba histolytica. The inhibitors are polymers of galactose that mimic the intestinal receptor for the amebic adhesin. Tracy discovered that for these compounds to be effective as inhibitors that it was necessary to preserve all of the OH groups on the sugar nucleus. Based on Tracy's work we have synthesized a new set of galactose polymers that are now being screened for therapeutic activity.

International Infectious Disease
Contact: William Petri, M.D., Ph.D.

Medicine residents have participated in both international clinical research in Bangladesh (Cynthia Snider), and lab-based research at UVa (Tracy Bercu) with me in the last year. The general theme is international infectious diseases, with specific projects in Bangladesh that include enteric and respiratory infection and malnutrition, and, in Charlottesville, molecular pathogenesis of amebiasis.

EAEC Diarrhea
Contact: James K. Roche, M.D., Ph.D. 924-9922, PIC 3902

Enteroaggregative E. coli (EAEC) is now recognized as an important cause of diarrhea in the developed world, and as a cause of persistent diarrhea with growth and intellectual short-falls in developing nations. A mouse model of the human disease has recently been developed in our laboratory, when mice are challenged in the neonatal period as well as just after weaning, much as in the human population. Outcomes include measures of the intensity of infection using quantitative PCR on stool and on tissue of mice taken at euthanasia.

A one month project would involve: 1) extracting DNA from tissue and stool of mice infected with EAEC or control bacteria; 2) performing PCR with organism-specific probes to quantify the level of infection; and 3) using the results to determine whether novel interventions might diminish or obviate infection in mice, and ultimately in humans. Interest and willingness but no special expertise are required.

Clostridium difficile
Contact: Jeffrey Tessier, MD

The background: An animal model of C. diff toxin A-induced colitis has shown that neurokinin 1 receptor (NK1R, the main receptor for substance P)-knockout mice do not develop the inflammatory changes and epithelial damage normally associated with C. diff toxin A (I attached the original JCI article for those interested). I have been interested in neurokinin-induced inflammation as it relates to B. anthracis edema toxin and have used NK1R antagonists to study the role of NK1R/substance P in toxin-induced inflammation. There is a FDA-approved drug, aprepitant (Emend), that is a non-peptide antagonist of the NK1R...this drug is currently used for the treatment of chemotherapy-induced nausea/vomiting (CINV). Hypothesis: Heme/Onc inpatients treated with aprepitant for CINV have a lower incidence and/or severity of C. diff colitis. Design: Retrospective matched case-control--cases will be inpatients treated with aprepitant at UVA (FDA approval was in 2006), controls will be matched for time as inpatient (i.e. risk period for C. diff exposure), antibiotic exposure, age/sex/race, mucositis severity. Dx of C. diff colitis will be based on toxin assay positivity. The limitations will have to do with the number of pts here who've received aprepitant, but there is potential for design of a prospective trial based on these results.

Clinical and Microbiologic Features of Clostridium difficile Infections at Augusta Medical Center
Contact: Cirle Alcantara Warren, M.D.

The purpose of this study is to investigate the clinical presentations of patients with stools positive for C. difficile toxins A and/or B, perform molecular characterization of the toxins (DNA extraction, PCR) and lactoferrin assay and correlate the presence or absence of the emerging strains with disease severity and outcome of the patients. This study has been expanded to include the correlation of systemic and local inflammatory cytokine pattern with disease severity in CDI.

Goodpasture's Syndrome
Contact: Kline Bolton, M.D.

We are interested in the molecular dissection of the epitopes involved in Goodpasture's syndrome, and the role of T regulatory cells in disease modification. Our experimental work involves a rat model of Goodpasture's disease which can be induced with a single peptide which induces intra- and intermolecular epitope spreading on GBM antigens.

Growth Hormone in CKD/Dialysis
GH Secretagogues in CKD
Use of an AGE Blocker in DM with Proteinuria
Various rat glomerulonephritis projects
Contact: Kline Bolton, M.D.

Histocompatibility Laboratory
Major Research Interest: IgM Anti-Leucocyte Autoantibodies (IgM-ALA)
Contact: Peter Lobo, M.D.

Clinical Projects

1. Use of increased prednisone dosing in chronic rejection to prolong kidney transplant survival.
2. Salvaging renal allografts undergoing rejections (e.g. humoral mediated) with a poor prognosis (i.e. humoral mediated).
3. Transplanting patients who prior to transplant are sensitized and who have anti-HLA antibodies reactive to donor - a setup for rejections with a poor prognosis.

Basic Science Projects

This exciting research is centered on probing the biological role of IgM anti-leucocyte autoantibodies (IgM-ALA). These antibodies are present in all humans and other animals and can be detected at high levels in newborns. IgM-ALA are normally present at low levels but increase in diverse inflammatory states, both infective and non-infective. We show that IgM-ALA comprise several different antibodies, each binding in a specific manner to a different cell receptor. These IgM autoantibodies, unlike disease causing IgG autoantibodies, do not activate complement at 37°C and hence are not cytotoxic to cells at body temperature. Thus far we have shown that IgM-ALA (i) bind to CD3, CD4, and chemokine receptors (ii) downmodulate co-stimulatory molecules e.g. CD86 (on APC), CD4 and CD2 (iii) inhibit T cell activation and (iv) inhibit chemotaxis of cells. Our research is based on the hypothesis that IgM-ALA are anti-inflammatory as transplant recipients with high levels of IgM-ALA pre-transplant are protected from rejections and this hypothesis may also explain why IgM-ALA increase in diverse inflammatory states. These non-cytotoxic pentameric molecules could provide an innate mechanism to block receptors involved in cell activation and chemotaxis.

Our research is therefore focused in three areas:

(1) To determine if IgM-ALA protect against rejections in a murine model of heart transplants.

(2) To determine if IgM-ALA protect against renal ischemia reperfusion injury (IRI) - this research is in collaboration with Dr. Okusa, who has nicely shown in a murine model that renal IRI is caused by inflammation that is mediated by glycolipid activation of dendritic cells and NKT cells. Glycolipids are released by ischemic tissue. We are using an IgM knockout murine model to study the role of IgM-ALA in protecting against inflammation mediated by rejection as well as renal IRI.

(3) To determine if IgM-ALA protect against HIV-1 infection. We have shown that IgM-ALA bind to CD4 and chemokine receptors CCR5 and CXCR4. These receptors are important for HIV-1 viral entry into cells. These observations prompted us to study the role of IgM-ALA in protecting against HIV-1 viral entry into cells. We are working on the hypothesis that high levels of IgM-ALA present in newborns and certain HIV-1 infected patients may explain (i) the low infection rate (28%) of babies from HIV-1 infected mothers who have not been treated and (ii) the cases of HIV-1 infected individuals who have non-progressive HIV-1 infection despite lack of therapy. We have already shown that IgM protects against HIV-1 infection of human leucocytes both in-vitro cultures and in an in-vivo murine model where human PBL are introduced into a SCID mouse.

A successful outcome of this research could lead to development of vaccines to maintain high levels of IgM-ALA to protect against rejections and progression of HIV-1 by inhibiting viral entry. Current HIV-1 vaccines designed to increase anti-HIV-1 antibodies and cytotoxic T cells have been unsuccessful as this virus chronically changes its envelope antigens. Blocking HIV-1 entry with IgM-ALA could circumvent this problem. Techniques used in our laboratory include flowcytometery, column chromatography to separate protein molecules, cell culture techniques, viral culture techniques and ELISA techniques.

Leukocyte Trafficking in Acute Renal Failure
Lysophingolipids in Acute Renal Failure
Adenosine and Renal Injury
Contact: Mark Okusa, M.D.

My laboratory is currently interested in understanding the immunological mechanisms of acute and chronic kidney disease and translating this knowledge to novel therapies. Acute renal ischemia-reperfusion injury (IRI) is due in part to inflammation as an important early event in the cascade of intracellular responses that ultimately result in apoptosis and necrosis. Over the past several years we have examined the role of bone marrow derived cells in the pathogenesis of IRI and how they participate in innate and adaptive immunity. Current projects funded by NIH include: 1) Leukocyte trafficking in acute renal failure. This project focuses on the role of: i) CD4+ cells as well as subpopulations of CD4+ cells including NKT cells in the pathogenesis of IRI, ii) monocyte/macrophage heterogeneity in the pathogenesis of IRI, iii) target of adenosine 2A agonists in reducing inflammation and injury. 2) Lysophingolipids in acute renal failure. In particular the participation of sphingosine 1 phosphate (S1P) and S1P receptors in the inflammatory process of IRI as well as small molecules that serve as potential therapies has become a major interest in the laboratory. 3) Adenosine and renal injury. We are investigating the role of A2A adenosine receptors in mitigating the inflammation that participates in the pathogenesis of diabetic kidney disease. In particular a novel area of study is the immunobiology of podocytes which are glomerular epithelial cells that functions as a critical element in maintaining the glomerular permeability barrier and injury to these cells leads to certain disorders including diabetic nephropathy. These non immune cells possess the costimulatory molecule B7.1 that may participate in danger signaling.

Laboratory methods: standard molecular and cell biological methods, siRNA, flow cytometry, adoptive transfer studies, whole animal studies, bone marrow chimeras and tissue specific gene deletion.

Representative Publications:

1. Yuan-Ji Day, L. Huang, Marcia J. McDuffie, Diane L. Rosin, Hong Ye, J.-F. Chen, M. A. Schwarzschild, J. S, Fink, J. Linden and M. D. Okusa. Chimeric wild-type/A2A-adenosine receptor knockout mice demonstrate that inflammatory cells are the target of A2A-agonist mediated protection of Ischemia-reperfusion injury in mouse kidneys. J. Clin. Invest. 112: 883-891. 2003.
2. Day, Y.J. M. Marshall, L. Huang, H. Ye, J. Linden and M. D. Okusa. Renal Ischemia-Reperfusion Injury and Adenosine 2A Receptor-Mediated Tissue Protection: The Role of Macrophages. Am J Physiol Renal Physiol. 2005 Apr;288(4):F722-31. Epub 2004 Nov 23.
3. Y.-J. Day, L. Huang, H. Ye, L. Li, J. Linden, and M. D. Okusa. Renal Ischemia-Reperfusion Injury and Adenosine 2A Receptor-Mediated Tissue Protection: the role of CD4 T Cells and Interferon gamma. J. Immunol. 176: 3108 - 3114, 2006.
4. Li, L. and Okusa, M.D. Blocking the Immune Response in Ischemic Acute Kidney Injury: The Role of Adenosine 2A Agonists. Invited Review Nature Clinical Practice Nephrology. In press 2006.
5. Sevigny, C*., Li Li*, A. Awad, L. Huang, M. McDuffie, J. Linden, P. I. Lobo and M.D. Okusa. Activation of Adenosine 2A Receptors Attenuates Allograft Rejection and Alloantigen Recognition J Immunol. 178(7):4240-4249, 2007. *Equal contributors as first author.
6. Li. Li, L. Huang, S. S.J. Sung, Randall Gregg, Vic Engelhard, P.I Lobo, M. D. Okusa. NKT cell activation of PMN Interferon gamma production Induces Injury following Ischemia-Reperfusion. J. Immunol. 178:5899-5911, 2007.
7. Awad, A.S. and M.D. Okusa. Distant organ injury following acute kidney injury. Editorial Comment. Am J Physiol Renal Physiol.2007; 293: F28-F29, 2007.
8. Alaa S. Awad, Michael Rouse, Lixia Liu, Amy L. Vergis, Diane L. Rosin, Joel Linden, John R. Sedor and Mark D. Okusa. Activation of podocyte adenosine 2A receptors prevents puromycin-induced nephrosis. J. Am. Soc. Nephrol. 19: 59-68, 2008.
9. Jo. S.-K, A. Bajwa, A. Awad, K. Lynch and M.D. Okusa. Invited review. Sphingosine 1-phosphate Receptors: Biology and Therapeutic Potential in Kidney Disease. Kidney Int. Kidney Int. 73, 1220-1230, 2008.

Biomarkers in Acute Kidney Injury
Contact: Mitchell Rosner, M.D.

Using cardiac bypass surgery as our model, patients at high risk for acute kidney injury (AKI) are identified. These patients are then enrolled and have sequential urine and blood drawn during their hospital stay. Blood and urine is assayed for an array of inflammatory cytokines (IL-1β, IL-6 and TNF-α) and these values are correlated to changes in serum creatinine using an area-under-the-curve model of analysis.

We are also investigating a novel urinary biomarker (ABP-26) for its utility in diagnosing AKI before detectable changes in serum creatinine (once creatinine levels begin to rise, most interventions are too late).

Finally, we are using urine proteomics to detect novel proteins that may serve as potential biomarkers of early AKI. There are also collaborative efforts with the NIH on assaying other urinary biomarkers.

Impact of IV Iron on Hospital Admission Rates
Contact: Mitchell Rosner, M.D.

We routinely give IV iron to patients with CKD or ESRD, but there is concern that this may lead to infectious complications. Using the CDR, we will look at subsequent admission rates for patients receiving IV iron at UVa.

Compliance in Taking Antihypertensive Medications
Contact: Mitchell Rosner, M.D.

Study of compliance in taking antihypertensive medications: goal is to randomly sample patients on > 4 antihypertensive medications who remain with uncontrolled hypertension and then use direct observation (ie. give the medications under direct view in the clinic) to assess true compliance. The goal will be to enroll up to 20 patients drawn from UMA. The hypothesis is that most patients on complex (>4 meds) regimens for BP control are more than likely non-compliant and when the drugs are given under direct observation, most patients will show either hypotension or good control.

Symptomatic Mild Hyponatremia
Contact: Mitchell Rosner, M.D.

To investigate whether mild forms of hyponatremia that are typically believed to be asymptomatic are really without symptoms. Patients with mild hyponatremia will undergo simulated driving tests. May also use tolvaptan to see if any deficits improve with treatment of hyponatremia.

Outcome of Hepatorenal Syndrome in Patients who Ultimately Undergo Liver Transplantation
Contact: Mitchell Rosner, M.D.

Review of data from combined UNOS/USRDS database evaluation to investigate if we can predict the factors that relate to renal function improvement after liver transplant and can develop a scoring system to evaluate which patients are likely to need renal transplant as well.

Role of Dialysate Glucose in Inflammation in Chronic Hemodialysis Patients
Contact: Mitchell Rosner, M.D.

It is well known that hemodialysis patients suffer from a morbid complex of problems termed the Malnutrition-Inflammation-Anemia (MIA) syndrome. The etiology of this underlying inflammatory state has not been well delineated but is likely multifactorial. This study attempts to assess the role of dialysate glucose concentrations in the pathogenesis of inflammation. Typically, dialysis patients undergo dialysis with a concentration of glucose at 200 mg/dL in their bath. This non-physiological concentration in vitro can activate cytokine production and we aim to test whether lowering the dialysate glucose concentration can lead to a reduction of plasma cytokine levels. Patients are enrolled with a cross-over design and thus serve as their own controls.

Use of Contrast Enhanced Ultrasound in Monitoring Changes in Renal Blood Flow After Physiologic Stimuli
Contact: Kambiz Kalantarinia, M.D.

Currently, I am doing a clinical study utilizing contrast enhanced ultrasound in monitoring the changes in renal blood flow after physiologic stimuli. This study is done in healthy volunteers and we measure Doppler velocities in proximal renal artery and also the blood flow to the cortex and medulla using contrast enhanced ultrasound. These tests are done at baseline and are repeated 2 hours after ingestion of a high protein (1.5 g/kg body weight) meal. I am almost 50% done with this project and one of my fellows is assisting me with it. I have an NIH grant and a Diabetes Center grant pending reviews working with the same technique in different disease states. If anyone is interested in renal physiology, especially measuring renal blood flow and using contrast ultrasound, we can get help from GCRC to design small and short term studies. If my grant applications are approved, then I have money to run new studies and can get residents involved in them.

The Role of Cytokines/Chemokines in Inflammation, Immunity, Trafficking of Circulating Progenitor Cells, Angiogenesis, and Cancer Metastases Relevant to Human Diseases
Contract: Robert Strieter

Our laboratory is interested in cytokine and chemokine biology as it relates to a variety of human diseases. We are currently investigating the role of a variety of cytokines (i.e., early response, Th1, and Th2) and CXC, CC, C, and CX3C chemokines in mediating inflammatory and immunologically mediated disease processes. Our laboratory is interested in the mechanisms of how CXC chemokines modulate angiogenesis and metastases of cancer; and promotes vascular remodeling in fibroproliferative disorders. Our laboratory was the first to discover that the CXC chemokine family can behave as either promoters or inhibitors of angiogenesis. We have determined that on a structural/functional basis the domain of three amino acids (Glu-Leu-Arg; ELR motif) that immediately precedes the first cysteine amino acid residue of the primary structure of these cytokines, dictates their function in regulating angiogenesis. Members of the CXC chemokine family that contain the ELR motif (ELR+) are angiogenic, whereas members that lack the ELR motif (ELR-) and are induced by interferons inhibit the angiogenic activity induced by either ELR+ CXC chemokines, bFGF, or VEGF. Furthermore, others and we have determined that specific chemokine receptors are involved in this disparate angiogenic activity.  Our laboratory is interested in mesenchymal progenitor cell trafficking during inflammation and resolution of injury. We are one of the first groups to show that these cells can contribute to the fibroproliferative phase of lung injury. We are expanding these findings to include understanding mechanisms of mesenchymal stem cell plasticity that may be relevant for pathogenesis of obesity. We have found that a circulating progenitor epithelial cell is necessary for repair of injury related to the airway or lung parenchyma epithelium. Our laboratory is interested in the role of cytokines/chemokines in mediating acute and chronic lung allograft rejection. We are one of the few laboratories in the country that has operative an orthotopic single lung transplantation model in rat.  Our laboratory uses a variety of strategies that include molecular, cellular, animal models, and human tissue specimens to examine the biology of chemokines in the regulation of innate and adaptive immunity, angiogenesis, and progenitor cell trafficking in a variety of model systems relevant to human disease.

Timing of Family Meeting Documentation in the MICU
Contact: Jonathon Truwit, M.D.

Evaluation of 1st documented family meeting in the medical record stratified by age, APACHE IV, and clinical outcome (mortality). This will involve looking for documented family meetings in the chart from a 4 year period to look if our clinical predictors (age, etiology of admission, and APACHE IV) push clinicians to have and document family meetings earlier in the chart. This will be a descriptive study. We will also look to see if increasing hand-offs changed the practice pattern.

ICU Outcomes Post Duty Hour Implementation
Contact: Jonathon Truwit, M.D.

This is an 800 patient chart review exploring the mortality and morbidity associated with increasing hand-offs in the MICU. We will be comparing outcomes stratified by APACHE IV score of patients admitted before and after July 1, 2004 (when the old night float system went into place). The study will end prior to the start of this academic year and will cover a 4 year period of patient admissions. In addition to mortality, we will be looking at LOS and 30-day mortality as well.

Top | Home