University of Virginia Health System

FOR IMMEDIATE RELEASE
Bob Beard
434-982-4490
bobbeard@virginia.edu

Basic Researchers at UVa Health System Keep Eyes on the Final Prize

Basic research work represents the oft-hidden genius of academic medical centers. Laboratories in which basic scientists work day after day, in many cases collaborating with physician scientists, are the sites where medical breakthroughs begin.

This is an exciting time for basic research at the Health System. In September 2005 we celebrated the groundbreaking for the Carter-Harrison Research Building - which will devote more than 100,000 square feet to research on vaccine therapy, immunology, infectious diseases, cancer and other areas of biomedicine. In December 2005, as part of a larger gift, the Ivy Foundation gave $25 million for a new translational research facility that will encourage collaboration among investigators and clinicians and will house programs that convert laboratory findings into new treatments, new medicines and new methods of prevention and early detection of disease.

UVa Health System would like to share some of our current basic research projects that could one day be translated into valuable tests or treatments for patients.

• Restoring Hearing Loss
  Scientists at the University of Virginia Health System have discovered a new protein that could one day show them how to restore genetic hearing loss due to genetic causes, the reason for half of the cases of hearing loss in children.  Profound, early-onset deafness is present in thousands of children and is traced to genetic causes in at least half of cases.  Jeffrey Holt, associate professor of neuroscience, and colleagues have discovered a protein called TRPA1 that has proven to be the essential link that allows the sensory cell in the ear to convert sound stimulus into an electrical response that can be transmitted to the brain so that sound can be perceived. Identification of this protein and the gene that encodes TRPA1 could bring future treatments for deafness. The protein TRPA1 works by forming a channel resembling a donut in the cell membrane of inner ear hair cells. "In the absence of sound, the hole is closed," Holt explained. "But when sound strikes the protein, the hole pops open like a trap door, allowing potassium and calcium ions to flood into the cells. Because these elements carry a positive charge, an electrical signal is generated which is relayed to the brain for interpretation." Now that this genetic link to deafness has been established, Holt said, geneticists can examine the gene encoding TRPA1 in deaf patients, some of whom he expects may have a mutated form of the TRPA1 gene. This could allow for the development of new gene therapies for deafness and balance disorders in the next five to ten years, Holt said.
  
  
• Finding the causes of vascular inflammation
  Inflammation is one of the major processes driving the development of atherosclerosis, the disease underlying strokes and heart attack. Dr. Klaus Ley, professor of biomedical engineering and molecular physiology and biological physics and director of the UVa Robert M. Berne Cardiovascular Research Center, studies the role of adhesion molecules and chemokines in the recruitment of inflammatory cells like monocytes and lymphocytes into the vascular wall. His lab has also discovered a major role for blood platelets in this process, a cell type that was previously only implicated in blood clotting, but also plays a key role in vascular inflammation. This research is being translated to directly benefit patients through the development of proteomics-based biomarkers that can predict response to treatment and monitor possible complications of cardiovascular disease.
  
  
• Targeting viruses and cancer cells
  Dr. Wladek Minor, a professor of molecular physiology and biological physics at the UVa Health System, is tearing apart proteins to figure out the relationship between their structure and function. His goal is to solve one of the greatest mysteries in drug design - how specific, targeted drugs can kill viruses or cancer cells by finding their way around the human body's complex chemistry and defenses. A 1997 paper by Minor and a colleague is one of The Scientist magazine's ten-most cited research papers of the decade. It details a computer program to process the data coming from X-ray experiments made on protein crystals. The program is used in over 1,200 laboratories worldwide. Minor and his laboratory collaborators have mapped more than 350 proteins in the last five years in 3-D using the technology.
  
  
• Advancing knowledge of the human epigenome project
  One of the most exciting recent developments in science is the sequencing of the human genome.  Scientists at the University of Virginia are going beyond the DNA sequence and are looking at the science of epigenetic signaling and regulation of gene expression.  Epigenetic signals can change gene expression without altering the DNA sequence, by "switching" genes on or off.  Determining how these signals work is expected to advance dramatically our understanding of many human diseases that are not purely genetic in nature, but are products of changes in gene expression.  Dr. Sepideh Khorasanizadeh, Associate Professor of Biochemistry & Molecular Genetics, is one of the leading researchers studying the chemical modification of histones, which are proteins that package the genome in spools. Chemical modifications of histones are dynamic events occurring inside the nucleus of each cell that lead to specific processes carried out by our genome.  Dr. Khorasanizadeh has worked in collaboration with other UVa structural biologists, including Drs. Fraydoon Rastinejad (Pharmacology) and Wladek Minor (see above). They use the tools of structural biology such as X-ray crystallography and magnetic resonance spectroscopy to reveal a clear picture of how these critical interactions occur.  Recent new discoveries made by these scientists were published in the December 2005 issue of Nature. Their findings have direct implications for the large-scale human epigenome project that is expected to pave the way for breakthroughs in understanding both normal and disease states, including cancer progression.
  
  
• Understanding the important interaction between healthy cells and dying cells
  Every day, millions of unwanted cells die because of a highly evolutionarily conserved process named apoptosis, or "programmed cell death." The recognition of such dying cells by healthy cells and their subsequent clearance is a fundamentally important process. The failure to promptly get rid of dying cells leads to chronic inflammation and autoimmunity. Kodi S. Ravichandran, Ph.D., professor at the UVa Beirne Carter Immunology Center, says, "We have recently identified several genes involved in engulfment of apoptotic cells (most notable being, ELMO and GULP). Using a combination of biochemical and functional studies, we have put into order the several proteins involved in this pathway. This pathway is highly conserved from worm to humans, such that we can introduce the human gene into the worms deficient in the homologue and rescue the defect. We are now addressing how understanding this pathway might be used to combat autoimmunity and inflammation. Our work would also have implications for boosting immune responses to tumor antigens after cancer chemotherapies (which leads to apoptosis of tumor cells) and may limit recurrences of cancer."

Please call 434-924-9241 to get photos to accompany your article: We have photos of Dr. Minor, Dr. Ley, Dr. Khorasanizadeh and Dr. Holt.

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