SPUR 2018 Projects: Medicine

Surgery | College of Medicine


Local Neurotrophin Delivery to Enhance Peripheral Nerve Regeneration
Jay Agarwal, Associate Professor

This project focuses on the local delivery of nerve growth promoting drugs at the site of peripheral nerve injury. We have received funding from the DOD and NIH to investigate both drug delivery device development and the efficacy of locally delivered small molecules and proteins. Our lab has developed a biodegradable nerve conduit that can predictably release drugs to the site of an injury using diffusion kinetics. The device is capable of functioning in gap injuries, crush injuries or in conjunction with autologous nerve grafts. Our lab has studied the device in a rodent sciatic nerve injury model and we have identified candidate drugs for local delivery.

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Internal Medicine | College of Medicine


SIRT5 in Acute Myeloid Leukemia
Michael Deininger, Professor

Acute myeloid leukemia (AML) has the most dismal prognosis of all blood cancers. More than 70% of AML patients will succumb to their disease. Treatment is still based on a chemotherapy regimen developed three decades ago and what little progress has been made is attributable to improvements in supportive care. Although most patients initially respond to therapy, leukemia stem cells survive in sanctuary sites of the bone marrow and eventually cause relapse and death. Intense research has identified the major DNA mutations in AML, but this knowledge has not led to therapeutic breakthroughs. To overcome this stalemate, our translational research team has screened primary AML cells (donated with informed consent by patients) to identify vulnerabilities that are independent of genetic mutations and persist despite protection afforded by the bone marrow. We have discovered that cells from most of the AML patients screened to date are highly dependent on SIRT5, an enzyme that regulates energy metabolism, while similar blood cells collected from healthy volunteers are not. Although these results have given us hope, SIRT5's exact role in AML is not at all clear at this point. Our lab is following several lines of investigation to understand why AML cell survival is dependent on SIRT5, and to identify the mechanisms that link depletion or inhibition of SIRT5 with AML cell death. The potential of this project to improve treatment strategies for AML has our lab enthused. We are excited to welcome a young scientist to learn about and contribute to this research.

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Orthopaedics | College of Medicine


Prediction of Hospital Readmissions for Precision Medicine
Man Hung, Associate Professor

When patients leave the hospital after surgery they expect to be on a path to better health. Unfortunately, up to 15% of patients are unexpectedly readmitted to the hospital within 30 days of discharge. Hospital readmissions are an enormous public health concern and cause excessive strain on healthcare resources. Readmissions for musculoskeletal and heart conditions in particular are both frequent and expensive, costing billions in medical expenditures each year. Orthopaedic and heart surgeries are in the top 20 costliest procedures. In order to reduce excess hospital readmissions, prediction models are needed to identify patients at high risk of readmissions and to intervene in a timely manner. Prior attempts to develop risk calculators have been limited by insufficient data sources or results that could not be tailored to an individual. To date, there has not been any models developed that have the capability to model hospital readmissions for orthopaedic and heart conditions, for all ages and for all payers using big data repository linking clinical and non-clinical variables for precision medicine. The proposed research seeks to develop models that can predict which patients will experience hospital readmissions in an effort to identify targets for intervention. Once completed, this work has the potential to improve health care quality, reduce cost, and improve patients' quality of life.

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Surgery | College of Medicine


Development of Infection-Free Percutaneous Osseointegrated Prosthetics
Sujee Jeyapalina, Research Assistant Professor

Osseointegrated (OI) percutaneous prostheses are directly anchored within the bone of the residual limb and utilize a percutaneous connection to the external artificial limb. The OI prosthetic limbs represent a promising alternative to conventional socket prostheses. Currently, there are three types of OI prostheses under clinical trial in the USA. Success of these trials will enable a wider use of this technology within the US health care system. Our research group consists of experienced clinician scientists, orthopaedic engineers and translational scientists. Our group is working to improve current OI prosthetic systems' longevity and functionalities. Our research activities include microbiome studies, histological analyses, animal model development, bio-ceramic, biomimetic coatings, implant designs and tissue phenotyping.

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Internal Medicine | College of Medicine


Salt and Water Homeostasis in Drosophila melanogaster
Aylin Rodan, Assistant Professor

Multicellular organisms maintain homeostasis of the internal milieu for optimal cellular functioning. This includes homeostasis of electrolyte concentrations, osmolality and pH. The kidney plays a central role in the maintenance of homeostasis through the regulation of transepithelial ion transport, the vectorial movement of water and ions across membranes. We study this process in the renal tubules of the fruit fly, Drosophila melanogaster. We have demonstrated a role for a chloride channel, bestrophin-1, in this process. We have also found that at the whole organism level, loss-of-function mutations in bestrophin-1 cause flies to die more quickly than wild-type when they are fed a high-salt diet. Ion transport occurs across different parts of the fly renal tubule, including the main segment and the lower segment, and also across the hindgut. Bestrophin-1 is expressed in all of these tissues. We would like to find out where bestrophin-1 is required in order for flies to survive on a high-salt diet. This will help us learn about ion transport processes important in iono- and osmoregulation. Perturbations of these processes in humans lead to electrolyte disorders, tonicity disorders and high or low blood pressure, which are frequent problems encountered in clinical practice that lead to patient morbidity and mortality.

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Internal Medicine | College of Medicine


The Effects of Recurrent Hypoglycemia on Neural Glucose Sensing
Owen Chan, Associate Professor

The importance of maintaining good glucose control over a lifetime of diabetes to avoid cardiovascular, renal and neurological complications has been well established by several landmark clinical trials. However, lowering glycemic goals for diabetic patients increases their risk for hypoglycemia ("low blood sugar") exposure. Hence, hypoglycemia is one of the most serious acute complications of insulin-treated diabetes and remains the limiting factor in maintaining proper glycemic control. The brain and in particular, the ventromedial hypothalamus (VMH), plays an important role in detecting when blood glucose levels start to fall and then activates the appropriate hormone responses to correct the decline. However, repeated exposure to hypoglycemia can impair the brain's ability to sense a fall in blood sugar levels. Our laboratory's primary focus centers around understanding how neurons in the brain detect hypoglycemia and coordinates an appropriate hormone response through the release of neurotransmitters. More importantly, we try to understand how recurring exposure to hypoglycemia and diabetes impact these sensing mechanisms and look for potential therapeutic targets that can prevent hypoglycemia. Our lab combines cutting-edge neuroscience and molecular genetic techniques with classic physiology to evaluate brain and peripheral metabolism. If hypoglycemia can be prevented, it will enable physicians to treat diabetes more aggressively and allow patients to achieve more optimal glucose targets, decrease the risk of diabetic complications and improve lifelong outcomes.

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Internal Medicine | College of Medicine


Alteration of Glycolysis/Pentose phosphate pathway in failing and recovering hearts
Stavros Drakos, Associate Professor

Remarkable improvements in myocardial structure and function have been reported in some advanced heart failure (HF) patients undergoing "mechanical unloading" induced by left ventricular assist devices (LVAD). Unlike other HF therapies, which have also been associated with significant myocardial improvement, this tractable and specific LVAD population provides us access to pre-treatment myocardial tissue from both responders and non- responders which has enabled us to start probing the "signature" of myocardium that has the potential to improve. Our central hypothesis is that refining this "signature" will lead to a rational therapeutic approach in severe HF and will reveal broader recovery principles applicable to all stages and severity of HF. We hypothesized that specific metabolic adaptations drive myocardial recovery. Our preliminary data after examining myocardial tissue from normal donors and LVAD patients suggests a post- LVAD mismatch in glycolytic versus mitochondria oxidative phosphorylation that may indicate increased flux through the cardioprotective pentose phosphate pathway. We will employ novel and powerful in vivo metabolic flux studies using stable isotopes, mitochondrial respiratory measurements and metabolomics to test this hypothesis.
This project offers a rare opportunity to closely integrate clinical function, structure and in vivo mechanistic studies in human HF and recovery. Novel biological insights that inform both our clinical and basic science understanding of myocardial recovery has the potential to inform our understanding of HF pathology and potential recovery throughout the continuum of HF severity and will impact our treatment and management of advanced HF patients.

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