Affiliate Programs
Research Opportunities

DEPARTMENT OF BIOLOGY

Dr. Robert H. Kretsinger -
Protein Structure, Function, and Evolution 

In collaboration with Carl Creutz in Pharmacology we have determined the crystal structure of the calcium bound form of annexin VI to 2.9 Å resolution. The structure consists of two discs (domains 1-4 and 5-8) that are tipped 90o to one another. Under some conditions the two discs lie on a lipid monolayer both in the same orientation; under other conditions disc 5-8 is flipped over to antiparallel, as seen in 3D reconstructions from electron micrographs of 2D crystals. The crystal structure of T356D, at 2.5 Å, intended to mimic phosphorylation, reveals five Ca2+ ions not found in the wild type annexin VI.

In collaboration with Ron Bauerle, Department of Biology, we have determined several crystal structures of the phenylalanine inhibited form of 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase from E. coli. DAHPS condenses erythrose-4-phosphate and phosphoenolpyruvate to form DAHP, the precursor of all aromatic compounds in bacteria and plants. The sites of E4P, Mn2+, and PEP are located near the C-end of a (b/a)8 TIM-barrel. We have determined the structure of DAHPS(Phe)*Mn*PEP with and without the feedback inhibitor, phenylalanine, bound and have traced the changes in conformation from the Phe site to the active site. E4P can no longer bind and the PEP flips its orientation in DAHPS upon binding of Phe 20 Å away! Numerous mutants of DAHPS have been analyzed in terms of these crystals structures. We have proposed a mechanism of enzyme action and a mechanism for feedback inhibition.

With Julie Sando, Anesthesiology, we have made 2D reconstructions from electron micrographs of protein kinase C-d, of its regulatory domain, and of PKCd complexed with myelin basic protein. The C1 domain of RDd is imbedded in the phospholipid monolayer. The binding of MBP to the catalytic domain of PKCd causes a shift in orientation of the catalytic domain relative to the regulatory domain. These E.M. studies are being extended to 3D. We anticipate being able to fit existing crystal structures of domains of PKC into the low resolution 3D model of the intact protein interacting with a membrane surface.

Our lab has a long standing interest in protein evolution; we have focussed on generating and interpreting dendrograms of EF-hand containing proteins as well as those with leucine rich repeats. We have promising results on a new program whose goal is ab initio prediction of protein structure. back to top

DEPARTMENT OF MOLECULAR PHYSIOLOGY
AND BIOLOGICAL PHYSICS

Dr. Brian R. Duling -
Cell-cell Signaling in the Microcirculation and Selective Genetic Manipulation of Connexin Expression

Much of cardiovascular pathophysiology derives ultimately from deranged function of either the smooth muscle or the endothelium of the microvessels. Our laboratory focuses on the means by which the cells of the arteriolar wall operate as a coordinated unit. Using video microscopy of living cells in situ, we operate at the interface between cell and integrative biology. State-of-the-art imaging technologies and computer processing, combined with newly developed cell-specific surface labels and detection indicators allow us to visualize the individual cells of the microvessel wall, as well as the formed elements of the blood in the living animal.

Using these tools, we have three major experimental efforts underway. First, we are attempting to understand the role played by the endothelial cell glycocalyx in the control of erythrocyte and leukocyte distribution in the mircrovessels. This work has special relevance to the factors which regulate tissue oxygen supply, and the permeability of the microvessels to solutes and water. Second, we are studying the chemical, mechanical, and electrical signaling processes, which establish cell-cell communications within and between smooth muscle and endothelial cell. Our special interest is in the role of gap junctions in the vessel wall. This work is facilitated by the use of cell specific regulation of gene knockout in smooth muscle and endothelial cells. Third, we are searching for the trigger mechanisms responsible for stretch and flow sensitivity of blood vessels. These three experimental programs are part of an ongoing effort to understand the vasculature as a communications network, and to discover how the functions of the vasculature are matched to the needs of the organ and organism. back to top

Dr. Klaus Ley

My scientific training and most of my research activities fall within the areas of physiology, vascular biology and biomedical engineering. Being an MD, I have always been interested in translating laboratory research findings back into clinical practice and/or engineering applications. My specific research interests include 
  • Molecular mechanisms of leukocyte and monocyte rolling, adhesion, transmigration, and matrix interaction
  • Role of leukocyte adhesion molecules and chemokines in atherosclerosis 2. Phenotype of gene-targeted mice deficient for leukocyte-endothelial cell adhesion molecules
  • Ultrasound-based imaging of inflammation using targeted microbubbles Biomechanics of leukocyte rolling and adhesion
  • Leukocyte adhesion molecules and chemokines in inflammatory bowel disease
  • Regulation of blood neutrophil counts in vivo 

An important laboratory technique is intravital microscopy. Other, more widely used laboratory techniques are molecular biology, biochemistry, flow cytometry, hematology, histology, immunohistochemistry, bone marrow transplantation, adoptive transfer, mass spectrometry, real-time RT-PCR and various cellular assays. Almost all my research projects make use of knockout and transgenic mice, most obtained from collaborators and some made in my laboratory. Other tools include monoclonal antibodies, peptides, and pharmacological inhibitors.

Recent publications in vascular biology: 

Ramos, C.L., Huo, Y., Jung, U., Ghosh, S., Manka, D.R., Sarembock, I.J., Ley, K. (1999). Direct demonstration of P-selectin- and VCAM-1-dependent mononuclear cell rolling in early atherosclerotic lesions of apolipoprotein E-deficient mice. Circulation Research 84: 1237-1244

Node, K., Huo, Y., Ruan, X., Yang, B., Ley, K., Zeldin, D.C., Liao, J.K. (1999). Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science 285: 1276-1279.

Huo, Y., Hafezi-Moghadam, A., Ley, K. (2000). Role of Vascular Cell Adhesion Molecule-1 (VCAM-1) and fibronectin connecting segment-1 in monocyte rolling and adhesion on early atherosclerotic lesions. Circ. Res. 87: 146-152

von Hundelshausen, P., Weber, K.S.C., Huo, Y., Proudfoot, A.E.I., Nelson, P., Ley, K., Weber, C. (2001). RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation, 103: 1772-1777 

Simoncini, T., Hafezi-Moghadam, A., Brazil, D., Ley, K., Chin, W.W., Liao, J.K. (2000). Vascular protective effects of oestrogen mediated by phosphatidylinositol 3-OH –kinase. Nature 407: 538-541.

Huo, Y., Forlow, S.B., Weber, C., Jung, S. Littman, D.R., Ley, K. (2001) The chemokine KC, but not MCP-1 triggers arrest of monocytes in carotid arteries with early atherosclerotic lesions. J. Clin. Invest. 108: 1307-1314.

Schober, A., Manka, D., von Hundelshausen, P., Huo, Y; Hanrath, P., Sarembock, I.J., Ley, K., Weber, C. (2002). Deposition of platelet RANTES triggering monocyte recruitment requires P-selectin and is involved in neointima formation after arterial injury. Circulation 106: 1523-1529

Prorock, A.J., Hafezi-Moghadam, A., Laubach, V.E., Liao, J., Ley, K. (2002). Vascular protection by estrogen in ischemia-reperfusion injury requires endothelial nitric oxide synthase. Am. J. Physiol., in press

Hafezi-Moghadam, A., Simoncini, T., Yang, Z., Limbourg, F.P., Plumier, J.-C., Rebsamen, M.C., Hsieh, C.M., Chui, D.S., Thomas, K.L., Prorock, A.J., Laubach, V.E., Moskowitz, M.A., French, B.A., Ley, K., Liao, J.K. (2002). Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nature Medicine 8: 473-479.

Huo, Y., Schober, A., Forlow, S.B., Smith, D.F., Hyman, M.C., Jung, S., Littman, D.R., Weber, C., Ley, K. (2002). Circulating activated platelets exacerbate atherosclerosis in apolipoprotein E deficient mice. Nature Medicine, in revision. back to top

Dr. Richard A. Murphy

The research interests in my laboratory are focused on the mechanism of chemomechanical transduction, the molecular regulatory mechanisms governing crossbridge interactions, and the role of molecular variants of contractile, regulatory, and cytoskeletal proteins in functional diversity in smooth muscle. These questions are
pursued by a multidisciplinary approach, including (1) biophysical analysis of the mechanical output of isolated smooth muscle, (2) biochemical studies of isolated proteins and of reactions such as crossbridge phosphorylation in intact tissue involved in regulation, (3) electrophoretic and immunological separation analyses of protein variants, (4) estimates of cell Ca2+, ATP consumption rates and the energetics of contraction from measurements of oxygen consumption or heat production, (5) structural studies, and (6) mathematical modeling of proposed regulating mechanisms. back to top

Dr. Gary K. Owens -
Molecular Regulation of Smooth Muscle Growth and Differentiation 

Regulation of Smooth Muscle Cell Differentiation
during Vascular Development and in Disease

A major focus of studies in our laboratory is to understand molecular mechanisms that regulate the growth and differentiation of vascular smooth muscle cells during vascular development and in vascular diseases such as atherosclerosis that are characterized by alterations in the control of smooth muscle differentiation. Current studies are aimed at identifying molecular mechanisms that control the coordinate expression of contractile protein genes such as smooth muscle *-actin and smooth muscle myosin heavy chains that are required for the differentiated function of the smooth muscle cell.

Studies involve use of a wide repertoire of molecular genetic techniques and include identification of cis elements and trans regulatory factors that regulate cell-type specific expression of smooth muscle differentiation genes both in cultured cell systems and in vivo in transgenic mice. In addition, we use a variety of gene knockout, chimera, and gene over-expression approaches to investigate the role of specific transcription factors and local environmental cues (e.g. growth factors, mechanical factors, cell-cell and cell-matrix interactions, etc.) in regulation of smooth muscle differentiation during vascular development, or in cardiovascular disease.

A particularly exciting recent development is that we have employed smooth muscle specific promoters originally cloned and characterized in our laboratory (see references 3 & 4) to create mice in which we can target knockout (or over-expression) of genes of interest specifically to smooth muscle cells (see reference 5). Such systems will permit development of unique and powerful genetic mouse model systems with which to directly explore mechanisms that contribute to vascular development, and remodeling in vivo, as well as to investigate the etiology of a variety of major cardiovascular diseases including hypertension and atherosclerosis. In addition, we have employed these promoters to develop methods for producing purified populations of smooth muscle cells or smooth muscle cell progenitor cells from both embryonic and somatic stem cells. The latter studies have tremendous potential for use in either correcting gene defects that contribute to cardiovascular disease, or alternatively delivering therapeutic genes to treat or possibly cure these diseases.

Representative Publications:

Owens, G.K.: Regulation of differentiation of vascular smooth muscle cells. [Review]. Physiol Rev 1995;75:487-517

Madsen,C.S.; Regan,C.P.; Hungerford,J.E.; White,S.L.; Manabe,I.; and G.K. Owens: Smooth muscle-specific expression of the smooth muscle myosin heavy chain gene in transgenic mice requires 5"-flanking and first intronic DNA sequence. Circ. Res. 1998; 82: 908-917.

Mack, C.P. and G.K. Owens. Regulation of SM alpha-actin expression in vivo is dependent upon CArG elements within the 5' and first intron promoter regions. Circ.Res. 84: 852-861, 1999.

Regan, C.P.; Manabe, I.; and G.K. Owens. Development of a smooth muscle targeted cre recombinase mouse reveals novel insights regarding mechanisms of smooth muscle myosin heavy chain promoter regulation. Circ. Res. 87:363-369, 2000.

Regan, C.P; Adam, P.J.; Madsen, C.S.; and G.K. Owens. Identification of molecular mechanisms that contribute to vascular injury-induced decreases in expression of smooth muscle differentiation marker genes in vivo. J. Clin. Invest. 106:1139-1147, 2000.

Manabe I., and GK Owens. Recruitment of SRF and hyperacetylation of histones at smooth muscle-specific regulatory regions during differentiation of a novel P19-derived in vitro smooth muscle differentiation system. Circ. Res. 88:1127-1134, 2001. back to top

Dr. Avril Somlyo

The molecular mechanisms of excitation-contraction coupling, contractile regulation and the basis of contraction in mammalian smooth muscle are the long-term interests of our laboratory. We are currently working on a new signal transduction pathway, which is activated when physiological transmitters or drugs bind to cell membrane receptors and lead to a marked increase in the sensitivity of the contractile proteins to calcium (Ca2+-sensitization). We have found that this G-protein-coupled process, which operates under physiological conditions, inhibits myosin light chain phosphatase, resulting in an increased population of phosphorylated (activated), cycling myosin motors. The phosphatase is a trimeric complex with a 110 kDa subunit which targets the activity to myosin. Current biochemical and molecular biological studies are directed to establishing the messengers between the membrane receptors/G-proteins and the myosin-associated phosphatase, as well as elucidating the mechanism of inhibition of the enzyme. The small G-protein RhoA and Rho-kinase participate in this signaling cascade. This same pathway modulates cell migration, and we are exploring its role in tumor cell metastasis. Biochemical and molecular biological techniques and physiological studies of permeabilized smooth muscle cells are used to identify the signaling molecules and their targets, as well as cross-talk among various other signaling pathways.

Transgenic and knockout mice are used to elucidate the role of telokin, a molecule found in small-but not large-blood vessels. Telokin is phosphorylated upon cyclic nucleotide-induced relaxation; we are testing the hypothesis that it functions by activating myosin phosphatase.

Contraction in smooth muscle, mediated by interactions between actin filaments and crossbridges on adjacent myosin filaments, is triggered by the rise in cytoplasmic calcium and consequent phosphorylation of the 20 kDa light chains of myosin. The crossbridges are the motors that utilize ATP as an energy source for the generation of force and work. The kinetics of this motor and its modulation in muscle are characterized in our laboratory by using photolysis of caged nucleotides, caged Ca2+ and caged Bapta and monitoring force and stiffness transients. We use a new, fluorescently labeled, genetically engineered mutant of a bacterial phosphate-binding protein to follow the kinetic relationship between force development and phosphate release from the ATP binding pocket of the crossbridge following photolysis of caged ATP. The rationale for studying crossbridge kinetics in permeabilized fibers, rather than in solutions of purified proteins, is that the biological ATPase cycle is modulated by the physical strain on the crossbridges. We have demonstrated that slow, tonic smooth muscles, unlike fast, phasic smooth muscles, have a high affinity for ADP and relatively low affinity for ATP, leading to prolongation of the strongly bound state in the crossbridge cycle and marked slowing of relaxation of force by MgADP. Current efforts are toward determining the myosin isoformic variations responsible for this high ADP affinity and its potential role in the maintenance of high force at low ATPase activity, a characteristic of the high economy of energy usage by smooth muscle.

Our goal for these studies is to understand the fundamental properties of the crossbridge motors, their differences and their regulation in fast and in slowly contracting smooth muscles. The long-term aim of our work is to provide insights into the abnormalities of disease states involving smooth muscle, such as hypertension.

Another focus in our laboratory is the mapping of subcellular calcium distribution and handling in cardiac muscle during physiological stimuli and calcium overload. Electron probe X-ray microanalysis is used to determine and image, at high spatial resolution, elemental distributions within cardiac muscle organelles and membranes. We are particularly interested in the affinity of mitochondria for calcium during normal systole and diastole and in the role of calcium binding to intercalated disks during cardiac arrhythmias. back to top

Dr. Gabor Szabo 

Molecular interactions in G protein coupled signal transduction

Integration of extracellular signals is an essential function of the plasma membrane. For heptahelical receptors this function is accomplished by heterotrimeric G proteins that couple receptor activation to specific effectors. A major objective of the laboratory is to understand the physicochemical basis of the molecular interactions taking place during this signal transduction cascade. Total internal reflection fluorescence microscopy (TIRFM) of supported membranes is used to investigate interactions of fluorophore-labeled G protein ? and ?? subunits with lipid membranes, either pure or incorporating molecules with which G proteins interact. Fluorescence intensity, fluctuation and energy transfer measurements are used to investigate molecular interactions in the membrane and to relate these to the structure of the protein and lipid components of the system.

Of particular interest are the functional roles of N-terminal myristoylation and thioacylation of G protein ?i/o subunits as well as lipids mimicking subdomains (rafts) of the plasma membrane. Proteins that associate with G proteins, including RGS, caveolin and a channel effector, are studied with respect to their effects on subunit lateral movement and interactions. In a complementary approach, excised patches of cell membranes expressing G protein-regulated muscarinic potassium channels (KACh) are used to assay the functionality of fluorescently labeled and/or chemically modified G protein subunits and to understand channel regulation in vivo on the basis of the TIRFM results. These studies are expected to establish a link between structural features of molecules participating in G protein coupled signaling and their functional dynamics.

Function of membrane proteins in pure lipid membranes

Synthetic lipid membranes made from pure lipids are used to understand the relationships between the structure and function of ion channels in membranes of well-defined composition. Channel forming molecules, including bacterial toxins and model peptides are incorporated in these membranes and studied under voltage clamp in order to understand their cellular function as it relates to their molecular structure.

Role of ion channels in the genesis and maintenance of atrial fibrillation

The laboratory is also interested to identify molecular events leading to a predisposition of the heart to atrial fibrillation (AF). Current focus is on atrial membrane currents that may be responsible for an increased vulnerability to fibrillation as well as the associated molecular and cellular factors that contribute to the maintenance and propagation of sustained AF. One of the goals of these studies is to design compounds that specifically target molecular pathways involved in the development of increased vulnerability to AF and test their efficacy. back to top

DEPARTMENT OF PATHOLOGY AND BIOCHEMISTRY

Dr. Steven L. Gonias

Cell surfaces and the pericellular microenvironment are sites rich in proteinases and proteinase inhibitors. Our major goal is to understand the macromolecular interactions which localize these proteins near the cell surface and understand how proteinases affect cell function. Our laboratory has characterized cellular binding sites for the proteinase, plasmin, on a variety of cell types including endothelial cells. Plasmin functions not only in fibrinolysis, but in processes that require cellular migration including angiogenesis and tissue remodeling. Very high concentrations of plasmins may be generated near the cell surface by plasminogen activators. A major focus for our group is to characterize growth factors and growth factor receptors as substrates for receptor-associated plasmin. Since most growth factors bind to multiple cellular receptors, we hypothesize that plasmin and other proteinases may alter cellular responsiveness to growth factors by specifically cleaving one of a group of receptors.

In related work, we are studying proteins which may serve to target growth factors to specific cell types. In particular, we are studying a2-macroglobulin, a proteinase inhibitor, which binds a variety of growth factors including transforming growth factor-b and platelet derived growth factor. a2-Macroglobulin synergizes the activity of growth factors towards cells that express the a2 macroglobulin receptor. The a2-macroglobulin receptor is also known as low density lipoprotein receptor-related protein (LRP). The complete growth regulatory loop includes growth factors a2-macroglobulin, growth factor receptors, and LRP. Not only are we interested in studying the function of the growth regulatory loop, but also the expression of each of the components. back to top  

DEPARTMENT OF PHARMACOLOGY

Dr. James C. Garrison - Mechanisms by which Hormones and Growth Factors Regulate Cell Function

The overall goal of our research is to elucidate the mechanisms by which hormones and growth factors regulate cellular function. Presently, our major effort is directed toward understanding how the family of seven transmembrane domain receptors interact with G proteins to generateintra cellular signals. We are currently pursuing two major projects.. spIn the first project, we are attempting to understand how the diversity of G protein \(*a and \(*b\(*g subunits leads to specificity intrans membrane signaling. By using cDNA clones coding for the multiple subunits of G proteins to over express the proteins in thebaculovirus/Sf9 insect cell system, we can obtain large amounts of Gprotein \(*a subunits or \(*b\(*g dimers of defined composition. Using these techniques, we have demonstrated that recombinant\(*b\(*g dimers of defined composition have differential abilities to support the interaction between \(*a subunits and receptors or to directly activate effectors. These exciting results provide a potential explanation for signaling selectivity in the intact cell. Thus, we are expanding our study of the functional differences of recombinant \(*b\(*g dimers to better understand the specificity of cell signaling.

One important issue is to define a functional role for \(*b\(*g dimers
containing divergent \(*b subunits such as \(*b\s-4\d5\u\s+4. Ourinitial results with dimers composed of the \(*b\s-4\d5\u\s+4\(*g\s-4\d2\u\s+4 subunits indicate selective coupling to the Gq \(*a subunit and activation of a restricted set of effectors. We are now studying a panel of dimers containing the \(*b\s-4\d5\u\s+4 subunit combined with various \(*g subunits for their ability to couple receptors to \(*a subunits an to activate effectors. We are also studying the function of the variant \ (*b\s-4\d3S\u\s+4 dimer, identified in hypertensive patients, which is missing one WD-40 repeat. In another aspect of this study, we are determining which domains of the \(*g subunit interact with receptors and effectors. By using a series of chimeric \(*g subunits containing switched N- and C-terminal domains from a pair of active and inactive \(*g subunits, we are examining the role of these domains using assays of receptor interaction and effector function.

The final area of this study examines the possibility that the prenyl group of the \(*g subunit participates in activating the \(*b\(*g dimer. Dimers containing \(*gsub units modified with the C\s-215\s+2 farnesyl group are usually less active than dimers containing \(*g subunits modified with the C\s-220\s+2 geranylgeranyl group. We are testing the recent observation that the prenyl group interacts directly with the \ (*b subunit to determine if the two lipids cause different conformational changes in the \(*b subunit. The approach is to make mutant \(*b subunits in which the prenyl group is not able to fold back into the \(*b subunit and test their activity in assays of receptorin teraction and effector function. .sp
In a second project, we are studying the cross-talk between the pathways activated by G proteins and those activated by oncogenes and mitogens. Historically, these pathways were considered very separate; however, there now appears to be significant crosstalk between them. Thus, occupation of G protein coupled receptors can stimulate the activity of tyrosine kinases, guanine nucleotide exchange factors and growth regulating pathways.

G proteins markedly stimulate the p110-\(*gisoform of phosphatidylinositol 3-kinase (PtdIns 3-kinase) leading to production of phosphatidylinositol (3,4,5) tris phosphate. This lipid is an important signal that activates the phosphatidylinositol dependent protein kinase, PDK-1, leading to activation of protein kinase B and a host of signaling events. The initial focus of our work is to understand the mechanisms by which G protein \(*a and \(*b\(*g subunits activate the PtdIns 3-kinase. We are determining the ability of pure, recombinant, G protein \(*a subunits and \(*b\(*g dimers of defined composition to activate the purified p110-\(*g isoform of PtdIns3-kinase. In another aspect of this project, we are determining the domains in the \(*b and \(*g subunits that activate PtdIns 3-kinase. We are using \(*b\(*g dimers with selected point mutations in the \(*b subunit in combination with mutated and/or chimeric \(*g subunits to evaluate the domains in the \(*b\(*g dimer which activate the PtdIns3-kinase.

In the final aspect of this project, we are attempting to understand how known regulatory mechanisms affect the activity of \(*b\(*g dimers on PtdIns 3-kinase. We are examining the role of protein phosphorylation in regulating PI 3-kinase both in terms of phosphorylation of the kinase itself and phosphorylation of the \(*b\(*g dimers which activate this effector. back to top

Dr. Kevin Lynch - Molecular Pharmacology of Lysophospholipid Mediators

The research efforts currently underway in my laboratory are focused on the molecular pharmacology of lysophospholipids. Lysophosphatidic acid and sphingosine-1-phosphate are structurally-related lipids that are prominent components of serum, and elicit a variety of responses (e.g., calcium mobilization, cytoskeletal rearrangements, growth, escape from apoptosis) from cultured cells. These effects are mediated by a set of at least eight G-protein-coupled receptors. We are interested particularly in developing a medicinal chemistry for the lysophospholipid mediators. For example, we have developed recently a series of 2-substituted N-acyl ethanolamide phosphate compounds that includes LPA receptor type selective agonists as well as LPA receptor antagonists. Such tools will provide insights into the roles of these mediators in physiologic and pathophysiologic settings.

Another area of investigation is the mechanism of action of the immune modulator, FTY720. This drug, after phosphorylation, is a potent sphingosine 1-phosphate mimetic that evokes a redistribution of lymphocytes from the circulating to secondary lymphoid compartments. We are now using our synthetic molecules to define what sphingosine 1-phosphate receptors mediate this phenotype as well as what kinases and phosphatases metabolize FTY720-like compounds. In exploring the structure-activity relationships of lysophospholipid mediators, we collaborate closely with Professor T.L. Macdonald's laboratory in the Department of Chemistry at UVA. Our research is supported by grants from the NIH and the pharmaceutical industry.

Selected Recent Publications:

Hooks, S.B., Santos, W.L., Im, D-S., Macdonald, T.L. and Lynch, K.R. Lysophosphatidic acid induced mitogenesis is regulated by lipid phosphate phosphatases and is Edg-receptor independent. J. Biol. Chem. 276: 4611-4621 (2001).

Im, D-S., Heise, C.E., Nguyen, T., ODowd, B.F. and Lynch, K.R. Identification of a molecular target for psychosine and its role in globoid cell formation. J. Cell Biol. 153: 429-434 (2001).

Heise, C.H., Santos, W.L., Schreihofer, A.M., Heasley, B.H., Mukhin, Y.V., Macdonald, T.L. and Lynch, K.R. Activity of 2-substituted LPA analogs at LPA receptors: Discovery of a LPA1/LPA3 receptor antagonist. Mol. Pharmol. 60: 1173-1180 (2001).

Im, D.-S., Clemens, J., Macdonald, T.L. and Lynch, K.R. Characterization of the human and mouse sphingosine 1-phosphate receptor, S1P5 (Edg-8). Biochemistry 40: 14053-14060 (2001).

Brinkmann, V., Davis, M.D., Heise, C.E., Albert, R., Cottens, S., Hof, R., Bruns, C., Prieschl, E., Baumruker, T., Hiestand, P., Foster, C. and Lynch, K.R. The immune modulator, FTY720, targets sphingosine 1-phosphate receptors. J. Biol. Chem. ((2002) in press).

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