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Research at Rush > Research Funding > 2010 Research Awardees > 2010 New Investigator Awardees
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Congratulations to our 2010 New Investigator Awardees!

Jaydeep P. Bardhan, PhD
Elena N. Dedkova, PhD
Sunit Singla, MD
Yejia Zhang, MD

Title: Advancing Wide-angle X-ray Solution Scattering (WAXS) For Studying Protein Function
PI: Jaydeep P. Bardhan Ph.D., Assistant Professor, Department of Molecular Biophysics and Physiology
Award: $25,000
Abstract: Biological molecules known as proteins play central roles in the processes of life, and many diseases involve changes in these proteins-for example, genetic mutations that lead to cancer. As a result, clinically meaningful mastery of these diseases requires thorough knowledge about how proteins function. Modern experimental techniques and computer simulations enable studies of unprecedented detail, and the grand challenge ahead of us is to integrate these necessarily incomplete pictures into a single coherent understanding. I am working to improve our knowledge of protein behavior using a relatively new experimental technique known as wide-angle X-ray scattering (WAXS), which offers highly sensitive data about a protein's structure. My collaborators and I have recently developed a theory and computer simulation method to predict WAXS of proteins, and we are now applying these methods to a broad set of medically important proteins. Our efforts will have a broad, sustained impact across medicine and biology in three different ways. First, WAXS study of clinically relevant proteins will directly support ongoing efforts to combat their associated diseases. Second, this work will support much-needed refinement of popular methods for studying biological molecules, including both experiments and theories. Finally, our use of WAXS to address important problems will accelerate its integration into the mainstream of biological science, stimulate the community to conceive new applications, and drive the method towards reaching its potential to transform our understanding of the molecular bases of disease.

Title: Depletion of mitochondrial polyphosphate as a novel protection strategy against ischemia-reperfusion induced cell death
PI: Elena N. Dedkova PhD, Assistant Professor, Department of Physiology and Molecular Biophysics
Award: $25,000
Abstract: The proposed project is designed to develop a possible novel protection strategy against ischemia-reperfusion induced cell death following myocardial infarction. Myocardial infarction or acute myocardial infarction, commonly known as a heart attack, is the interruption of blood supply to parts of the heart, causing heart cells to die. This is most commonly due to occlusion (blockage) of a coronary artery following the rupture of a vulnerable atherosclerotic plaque, which is an unstable collection of lipids (fatty acids) and white blood cells (especially macrophages) in the wall of an artery. The resulting ischemia (restriction in blood supply) and oxygen shortage, if left untreated for a sufficient period of time, can cause damage or death (infarction) of heart muscle tissue (myocardium). Ischemic heart disease is the leading cause of death in the industrial world. The treatment of acute ischemic heart disease has entered a new era in which mortality can be approximately halved by procedures that allow the rapid return of blood flow to the ischemic zone of the myocardium, i.e., reperfusion therapy. Reperfusion, however, may lead to further complications such as diminished cardiac contractile function (stunning) and arrhythmia. Moreover, there is experimental evidence that irreversible cell injury leading to necrosis and apoptosis may be precipitated by reperfusion, known as ischemia-reperfusion injury (RI). Therefore, development of cardioprotective agents to improve myocardial function, decrease the incidence of arrhythmias, delay the onset of necrosis, and limit the total extent of infarction during ischemia-reperfusion is of great importance. Earlier pharmacological approaches to attenuate the consequences of RI have been of limited experimental efficacy or have failed to translate into useful clinical treatments. At present it is widely accepted that mitochondrial permeability transition pore (mPTP) opening contributes to the loss of cell viability associated with post-ischemic reperfusion. We propose that mitochondrial inorganic polyphosphate (poly P) plays an important role in mPTP opening. Therefore, depletion of the mitochondrial poly P levels either by poly P hydrolysis by exogenous enzymes or through stimulation of endogenous pathways would lead to the inhibition of the mPTP and consequent prevention of cell death following ischemia-reperfusion. This approach creates a new exciting possibility to develop an alternative treatment strategy against cell death following myocardial infarction.

Title: Intersectin-1 and LPS-induced Pulmonary Changes
PI: Sunit Singla, MD, Assistant Professor, Department of Medicine, Section: Pulmonary/Critical Care Med.
Award: $25,000
Abstract: Acute lung injury is an under-appreciated but frequent complication of cancer and infections. The most well known example is its role in causing the critical illness seen in patients afflicted with H1N1influenza. When it occurs, it most often limits the ability to treat the underlying disease contributing to a high rate of mortality. No specific therapy currently exists for this critical illness, and efforts to reduce its burden have been limited by an incomplete understanding of its mechanisms. Pulmonary microvascular endothelial cells make up the delicate lining of blood vessels throughout the lung and are thought to be a involved in the development of lung injury. Many of the critical functions of these endothelial cells, including cell survival and molecule transport, are regulated by the versatile protein, intersectin-1s. When these functions are disrupted by infection, the clinical manifestations of lung injury occur. By examining the downregulation of intersectin-1s during infection, and studying the consequent changes in molecule transport function, this project aims to better understand the mechanisms of lung injury. Based on this study's findings, new therapeutic strategies for lung injury may be developed in order to reduce the mortality of this otherwise devastating condition.

Title: Role of Fibronectin in Human Intervertebral Disc Pathophysiology
PI: Yejia Zhang, MD, Assistant Professor, Department Orthopedic Surgery
Award: $25,000
Abstract: Back pain is a common clinical problem with an enormous socio-economic impact in today's aging population. According to the United States Bone and Joint Decade report, estimated annual direct medical costs for all spine related conditions for the years 2002-2004 were $193.9 billion in the US. Few treatments designed to address the underlying pathology are available because the mechanism of disc degeneration is unclear. A further understanding of the molecular basis of disc degeneration is crucial to the design of effective therapeutic approaches for this disease.

Fibronectin is a large extracellular matrix protein that is found readily in the human intervertebral disc, a shock absorbing tissue lying between the vertebrae. The abundant extracellular matrix is made up of various proteins that provide the scaffold that supports cell adhesion, migration, proliferation, and differentiation. Fibronectin has many functional domains allowing it to bind to both cell surface proteins and extracellular matrix proteins. Although a large body of knowledge about fibronectin exists in other biological fields, little is known about its forms and functions in the human disc. Studies done by Dr. Oegema and colleagues have shown that in the human intervertebral disc, there is a correlation between the severities of disc degeneration and increases in the levels of fibronectin fragments generated by proteolytic enzymes. In our studies, we will identify which fibronectin fragments progressively accumulate in degenerative human intervertebral discs and determine how these fibronectin fragments are generated. Previous studies by our research group have shown that a chemically generated 29 kDa fibronectin fragment can cause disc degeneration when injected into a rabbit intervertebral disc. Once we identify naturally occurring fibronectin fragments, we will further investigate how these fragments can cause disc degeneration.

For these studies, human intervertebral disc tissues will be collected from patients undergoing surgery for treatment of symptomatic degenerative discs or spinal trauma. The severity of degeneration will be graded by routine magnetic resonance imaging (MRI). Using protein analysis of these tissues, we will determine which naturally occurring fibronectin fragments accumulate in more degenerative discs. Recently, we have identified a naturally occurring fibronectin fragment with an apparent molecular weight of 25 kDa in the human intervertebral disc. By analyzing these fibronectin fragments and identifying the site of cleavage, we will be able to determine which matrix-degrading enzymes play a key role in generating these fragments. By injecting these specific fibronectin fragments into human disc explant cultures, we will determine which naturally occurring fibronectin fragment can cause disc degeneration. These findings will help develop inhibitors capable of blocking the specific degrading enzymes and designing small molecules effective in blocking the biologic action of the most harmful fibronectin fragments.

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