MSSRP available projects – 2018

New MSSRP projects are posted when received from faculty, and retired as students match with preceptors.  The deadline for matches is April 30, 2018.


Faculty:  Mark Okusa, MD
Department:  Medicine/Nephrology
Contact:  924-2187/email:  mdo7y@virginia.edu
Project title:  Acute Kidney Injury
Project description:
Project 1: Pannexin 1 and Acute Kidney Injury. Panx 1, a channel able to release large amounts of ATP to the extracellular space, regulates vital processes including but not limited to ion transport, blood pressure and immune cell activation through purinergic P2Y and P2X receptor activity. Pharmacological inhibition of Panx 1 or global, endothelial and epithelial tissue specific deletion of Panx1 protects mice from ischemia-reperfusion injury. In cultured cells Panx1 deletion or overexpression leads to reduced or increased injury, respectively. Therefore, blocking Panx1 is a promising therapeutic strategy, and research centered around ubiquitously expressed pannexin 1 may contribute not only to the field of nephrology, but also to development of a therapeutic strategy against other acute organ dysfunctions.

Project 2: Ultrasound for Non-Invasive Prevention of Acute Kidney Injury. This project focuses on a novel approach to modulate inflammation through neural control of inflammation and acute kidney injury; a simple ultrasound (US)-based protocol that reduces tissue and systemic inflammation and prevents ischemia-reperfusion injury (IRI) in mice. This effect was a dependent affect which appears to be through the activation of the splenic cholinergic anti-inflammatory pathway (CAP). Our studies will define US characteristics to demonstrate a biomechanical effect to protect kidneys from IRI, define mechanistically the contribution of the CAP to protection from AKI through a unique optogenetic approach to specifically stimulate or silence splenic innervation, and establish the efficacy of US in relevant models of AKI including IRI and septic AKI in mice and AKI in pigs to enable transition to clinical trials in humans. Concepts and therapeutic principles could be pertinent to sepsis, colitis, myocardial ischemia, and arthritis

Project 3: Sphingolipids in Acute Kidney Injury and Disease Progression. Regardless of the cause of injury there is a stereotypical response leading to interstitial fibrosis. A key feature is the activation of extracellular matrix-producing myofibroblasts. Sphingosine 1-phosphate (S1P), a pleiotropic lysophospholipid that is involved in diverse functions such as cell growth and survival, lymphocyte trafficking, and vascular stability, has profound effects on the immune system and kidney injury. S1P is the product of sphingosine phosphorylation by two sphingosine kinase isoforms (SphK1 and SphK2) that have different subcellular localizations. We observed that Sphk2-/- mice had markedly attenuated renal fibrosis compared to Sphk1-/- or WT mice and marked tissue elevation of interferon gamma. These findings led us to focus our effort on the specific role of SphK2 and determine whether intranuclear SphK2 regulates tissue fibrosis.

Project 4: Leukocyte trafficking in acute kidney injury Acute kidney injury may progress to chronic kidney disease. Progressive fibrosis, a hallmark of chronic kidney disease, is characterized by deposition of extracellular matrix by myofibroblasts. Mechanisms underlying these maladaptive repair processes are not well understood. We provide evidence that deletion of CD73, an enzyme that converts AMP to adenosine on the extracellular surface, in perivascular cells (pericytes and fibroblasts), the cellular precursors to myofibroblasts, may have therapeutic value as a target after injury to prevent progressive fibrosis.


Faculty:  Charles Landen, MD
Department:  Obstetrics and Gynecology/Cancer Center
Contact:  243-6131/email:  clanden@virginia.edu
Project title:  Ovarian Cancer
Project description:  Laboratory research examining novel drugs this might increase sensitivity to conventional chemotherapies in ovarian cancer.


Faculty:  Joel W. Hockensmith, PhD
Department:  Biochemistry and Molecular Genetics
Contact:  924-5673/email:  jwh6f@virginia.edu
Project title:  Identification of Pharmacological Interventions
Project description:  Identification of Pharmacological Interventions for ATP-dependent Chromatin Remodeling DNA-dependent enzymes hydrolyzing ATP play critical roles in all DNA metabolic processes (e.g. replication, recombination, transcription, etc.) . Consequently, selective control of one subtype of these enzymes could play an important role in controlling processes that run rampant in cell growth and therein provide mechanisms for control of diseases such as cancer. One subfamily of the DNA-dependent ATPases is the ATP-dependent chromatin remodeling proteins belonging to the SWI/SNF family. Our laboratory has developed novel, naturally-occurring inhibitors of this family of proteins which has been used to control nucleosome remodeling, transcription and a variety of other processes. An example of the utility of these inhibitors is demonstrated in triple-negative breast cancer (TNBC) wherein multiple drug resistant (MDR) pumps are upregulated resulting in cellular resistance to traditional chemotherapy but our inhibitors alter chromatin remodeling therein decreasing transcription of MDR mRNA and reducing production of MDR proteins. The result in cell culture is that all tested TNBC cell lines become sensitive to standard chemotherapy (e.g. 5-fluorouracil, cisplatin, paclitaxel, etc.). The project entails final purification and identification of the precise chemical structure of the inhibitors using column chromatography and specifically HPLC.


Faculty:  Golam Mohi, PhD
Department:  Biochemistry and Molecular Genetics
Contact:  924-5657/email:  gm7sj@virginia.edu
Project title:  Identify new therapeutic targets and develop novel therapeutic strategies for treatment of MPNs/leukemia.
Project description:  My laboratory focuses on understanding the molecular and epigenetic mechanisms involved in the regulation of normal hematopoiesis (blood cell development) and hematologic malignancies (leukemia). JAK2, a member of the Janus family of non-receptor protein tyrosine kinases, is activated in response to a variety of cytokines. A somatic JAK2V617F mutation has been found in a majority of patients with myeloproliferative neoplasms (MPNs). One of the major interests in our lab is to study the role of the JAK/STAT signaling in the pathogenesis of MPNs. We are also investigating the interaction of epigenetic modulators with the JAK2 mutation in MPNs using state-of-the-art techniques and genetically engineered animal models. The ultimate goal of our research is to identify new therapeutic targets and develop novel therapeutic strategies for treatment of MPNs/leukemia.


Faculty:  Amy Mathers, MD
Department:  Medicine/Pathology
Contact:  982-4814/email:  ajm5b@hscmail.mcc.virginia.edu
Project title:  Increasing carbapenem resistance in Enterobacteriaceae
Project description:  Focusing on the urgent clinical problem of increasing carbapenem resistance in Enterobacteriaceae we have been evaluating detection methods in clinical microbiology and molecular transmission of carbapenemase genes for the last ten years. Molecular characterization has included analysis of mobile resistance mechanisms with evaluation of plasmid evolution and mobility across species with next generation sequencing paired thoughtfully with more traditional techniques. With the recent finding of involvement of the environment as a reservoir for drug resistant organisms my laboratory have expanded to work with Department of Engineering (Biomedical, Systems and Information and Material Science) at University of Virginia to establish natural history, models of dissemination as well as test interventions. The aim of my laboratory research is to aid in understanding the detection and microbial transmission of genetic mechanisms of resistance from the hospital environment to patient and thereby understand the scope and challenges of this growing crisis in health care.

One project would be laboratory based evaluation of various factors governing of rate and maintenance of plasmid mobilization between bacterial strains and species. Basic bacterial culture and molecular techniques would be used. Also basic understanding of DNA sequence interpretation and comparative genomics.

Another project will be to understand the correlation between susceptibility testing done in a clinical laboratory and the resistance prediction from whole genome sequencing evaluation on Gram negative bacteria.


Faculty:  Petr Tvrdik, PhD
Department:  Neurological Surgery & Neuroscience
Contact:  (801) 739-2650/email:  tvrdik@virginia.edu
Project title:  Role of Microglia in the Pathophysiology of Ischemic Stroke
Project description:  To elucidate the role of microglial calcium signaling in stroke, mouse models of ischemic injury will be studied with intravital imaging, single cell sequencing and other molecular biology techniques. We have discovered that microglia display waves of synchronized calcium activity during the progression of ischemic injury following middle cerebral artery occlusion (MCAo). Two-photon in vivo imaging and extracellular electrophysiology will be employed to study the activity patterns. Calcium channel inhibitors and genetic knockouts will be used to evaluate the significance of calcium signaling on cell activation and ultimately on the infarct size. In a parallel research project, mentored by Dr. Yashar Kalani, Wnt-dependent activation of stem cells after ischemic stroke will be traced with Axin2-lacZ and Axin2-CreER genetic tools and investigated with immunohistochemistry, in situ hybridization and whole transcriptome profiling. Access to perioperative clinical samples will allow us to correlate and extend the findings from mouse models to human pathology.


Faculty:  Gorav Ailawadi, MD
Department:  Surgery
Contact:  924-5052/ga3f@virginia.edu
Project title:  Surgical Innovation & Device Design
Project description:  Many of today’s complex medical problems are being solved at the intersection between engineering and medicine. Surgeons and other physicians who perform technical procedures work with sophisticated devices and other equipment – a direct example of the engineering-medicine interface. In 2016, the Surgical Innovation Program was launched to capture and develop new ideas for innovative technology and devices that could improve efficiency, ensure greater patient safety, lower costs and improve overall patient outcomes. Students will work alongside surgeons, interventionalists, other clinicians and engineers to develop new devices to solve real-world problems. Work will include, researching a problem statement for a new device, conducting market research, preparing concept sketches, and preparing low-fidelity prototypes through a rapid design process over the course of 7 weeks. Preferentially, we are seeking students with a background in engineering disciplines (for example, Biomedical, Electrical, Mechanical, and Materials).


Faculty:  Rita Basu, MD
Department:  Medicine/Endocrinology
Contact:  924-5780/email:  basu.rita@virginia.edu
Project title:  Integrated Physiology Diabetes Translational Program
Project description:  The Integrated Physiology Diabetes Translational Program provides an opportunity to learn and experience research in pathophysiology of carbohydrate metabolism, diabetes technology, and translational relevance of the findings. This program provides the necessary tools for acquiring professional skills in clinical and translational research in carbohydrate metabolism.

Students will be actively involved with all aspects of research studies related to our grants and awards. Students will interact with lab technologists and RN staff to better understand the technical aspects of laboratory based assays and gain hands on experience on instrumentation use for metabolic studies. Students will learn how to write up study protocols and associated documents required for CTSA and Institutional review board approval. He or she will assist the study RN coordinators and study PI’s in all aspects of conduct of study including subject screening, physical exams, review of medical records, and laboratory data.

Students will regularly and actively participate in Endocrine Research Unit seminars and Divisional scientific meetings to become well versed with research work from other endocrine labs and also learn presentation skills at these meetings.

Each student will be assigned a primary project related to grant specific aims. They will assist in the patient studies and observe how to perform insulin-glucose clamps, OGTT, IVGTT, MMTT, exercise VO2 max, and other metabolic procedures frequently utilized in this grant and other related projects to evaluate pathophysiology of pre-diabetes and type 2 diabetes.

They will also learn to write abstracts and manuscripts related to the grant work.
We anticipate that their time spent in the program will enhance their skills and prepare them for advancing their career in medicine. The student will not be making clinical decisions or providing patient care.


Faculty:  John F Angle, MD
Department:  Radiology and Medical Imaging
Contact:  924-9279/email:  jfa3h@virginia.edu/
Project title:  Patient Education Videos
Project description:  Many proceduralists have adapted educational videos for patient preparation and consent. What isn’t known is what elements are helpful to patients, their physicians, and to providing informed consent. Students will create three versions of an educational video about an IR procedure and survey patients before and after viewing the video. Some interest in making and editing a video will be required.


 

 

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