Research — Medicine

(M25 900)

Dana R. Abendschein, PhD
9924 Clinical Sciences Research Building
314-362-8925

Research in this translational physiology laboratory is focused on development of novel antithrombotic approaches for use during acute myocardial infarction, stroke, and surgery where vascular injury is an underlying mechanism. Current studies are designed to define the efficacy of targeting antithrombotics to the surface of injured vascular cells and activated platelets on thrombus progression. One approach uses nanoparticles covered with epitopes to bind exposed receptors on thrombus and containing inhibitors of coagulation or platelet activation. Students will be expected to participate in experiments using animal models and will develop skills in experiment design, vascular physiology, clinical antithrombotic therapy, coagulation, histopathology, and statistics.

John P. Atkinson, MD
10th Floor Clinical Sciences Research Building
314-362-8391
A clinical research elective is offered in the evaluation of patients with complement deficiency or overactivity states and with undiagnosed rheumatic disease syndromes.

Roberto Civitelli, MD
BJCIH 11th Floor, Musculoskeletal Research Center
314-454-8408
The biology of cell-cell interactions and communication in bone via gap junctions and cell adhesion molecules. Function of connexins and cadherins in transcriptional control of osteoblast differentiation, osteoclastogenesis, and mechanotransduction. Modulation of mesenchymal lineage allocation and osteogenic differentiation by cadherins and beta-catenin signaling.

Nicholas O. Davidson, MD
910 CSRB North Tower
314-362-2027
Genetic pathways for nonalcoholic fatty liver disease (NAFLD) and colorectal cancer development. We have two major areas of research interest. Our laboratory is interested, first, in the molecular mechanisms of hepatic steatosis, and the pathogenesis of NAFLD. This is the most prevalent liver disease in the US, likely affecting a quarter of the population. We have generated genetically manipulated mouse strains that offer insights into the mechanisms of hepatic steatosis. The student would work as part of a team, designing and conducting experiments that will test hypotheses concerning the mechanisms and consequences of hepatic steatosis. These studies will primarily involve mouse genetics, examining the expression of candidate genes under a variety of nutritional and pharmacologic settings that modulate hepatic lipid metabolism. In addition we are using microarrays to study the spectrum of genetic changes that may predict the extent of hepatic lipid accumulation in patients with steatohepatitis. Our goal is to test hypotheses using mouse genetics and to extend these studies to examine the same pathways in humans with NAFLD. Our second area of interest concerns the genetic pathways involved in colorectal cancer, the second leading cause of cancer-related deaths. We have developed a novel strain of mice in which the dominant effects of mutations inf the APC tumor suppressor gene have been abrogated through deletion of an RNA binding protein, apobec-1. This deletion has a major effect on the expression of cox-2, abrogating the increase in expression seen in human colonic adenomas and wild type mouse intestinal adenomas. These findings suggest that apobec-1 is a genetic modifier of colon cancer development. We will study the importance of apobec-1 expression in human colon cancer specimens and continue our murine genetic studies of this novel pathway for modulating colon cancer development and progression.

Thomas M. DeFer, MD
6604 Wohl Hospital
314-362-8050, tdefer@dom.wustl.edu
Special Projects in Medical Education. Through special arrangement with and approval by the Course Master, 4th year students will participate in special projects in medical education. Typical projects will require approximately four weeks to complete. These four weeks can occur consecutively (preferred) or be spread out somewhat as needed. Medical education projects should be aimed at improving the curriculum, student experience, and/or administration of the Internal Medicine Clerkship or the Subinternship. Interested students should contact the Course Master via phone or e-mail to discuss the proposed project. Those who are interested but would like guidance in designing a project should also contact the Course Master. This is open only to Washington University School of Medicine students.

Matthew Ellis, MB, BChir, PhD
Room 724, Southwest Tower
314-747-3613
Genomics of Breast Cancer. The demonstration that the HER2 gene was amplified in breast cancer heralded the “genomic era” for this disease which ultimately led to major clinical advances for HER2-positive disease.  The HER2 discovery was based on a search for cancer specific anomalies in the cellular homologs of the acutely transforming retroviral oncogenes described in birds and mammals.  However HER2 gene amplification is now recognized to be only one of a large number of somatic mutations that occur in breast cancer.  In the last ten years, my clinical and laboratory efforts have focused on the development of a luminal (hormone receptor positive) breast cancer genome atlas to elucidate the complexity of the somatic changes in the breast cancer genome responsible for tumors resistant to current therapies.  During these efforts we established a body of work on the practice of treating postmenopausal women with large palpable hormone receptor rich tumors with four months of an aromatase inhibitor.  The ultimate scientific goal of these efforts is to create specimen banks and biomarker data from thousands of patients to create sufficient statistical power to robustly link genomic screens to clinical outcomes so we can eventually focus our basic science efforts on the most lethal genetic events.

Over the last year, we have undertaken a comprehensive analysis of the tumor samples accrued, including “whole genome” gene expression chips, high resolution array comparative hybridization analysis and candidate gene sequencing. The gene lists we are currently generating, particularly those from the marriage of expression profiling and array comparative hybridization, suggest a host of new therapeutic targets are ready to be exploited.  Functional characterization of these genes has begun, and this effort is a major focus in the laboratory. Elective students will focus on projects that relate to individual oncogene candidates.  The scope of the project will be commensurate with elective time commitment but participation may include interpretation of genomic data, confirmatory studies on gene over-expression in cell lines and tissues and functional studies using gene transfer, gene knock-down and pharmacological targeting to verify the identity of bone fide therapeutic targets for further investigation.  Attendance at weekly lab meetings is expected.

Bradley Evanoff, MD, MPH
314-454-8638
Occupational medicine epidemiology and intervention research. My research involves the use of epidemiology methods to characterize associations between diseases and work-related exposures. I am also doing workplace intervention studies to prevent injuries and illnesses, and to improve healthy diet and physical activity among working populations. During an elective in occupational medicine epidemiology research, students will learn how to use epidemiologic methods to investigate disease processes by working on a mutually agreed-on topic of interest related to occupational diseases. Other activities can include work site visits and intervention projects, as well as involvement with work site health promotion and policy making. Elective length is variable depending on individual circumstances. Please contact Dr. Evanoff to discuss this research.

Gregory I. Goldberg, PhD,
7740 Barnard
314-362-8172
Role of secreted extracellular matrix metalloproteases in tissue remodeling. Structure and function of the metalloproteases.

Richard W. Gross, MD, PhD
4525 Scott Avenue, East Building
314-362-2690
Lipid mediators of signal transduction in the cardiovascular system. Characterization of regulatory mechanisms responsible for the liberation of lipid second messengers during cellular activation. The roles of phospholipases in mediating the metabolic syndrome and end-organ tissue damage.

Marc R. Hammerman, MD
7704 Wohl Clinic
314-362-8233
Studies characterizing the transplantation of kidney and pancreatic anlage as a means to “grow new organs” in the settings of end-stage chronic renal failure and diabetes mellitus.

Stacey House, MD, PhD
houses@wustl.edu, 314-362-8070
or Lisa Hayes, hayesli@wusm.wustl.edu, 314-362-4362
Emergency Medicine Clinical Research.  Emergency medicine clinical research involves the gamut of research designs ranging from retrospective cohort studies (The Use of B Hydroxy Butyrate Point-of-Care Testing in Diabetic Ketoacidosis), to prospective clinical trials (Biomarkers in Traumatic Brain Injury), to the evaluation of healthcare systems and Emergency Department processes (Effects of a Triage Process Conversion on the Triage of High Risk Presentations.), to analyzing health policy issues (Rate of Follow-up to a Primary Care Clinic and Subsequent Emergency Department Utilization among an Urban ED Population).  Students will learn the basic clinical research designs and will be able to articulate the benefits and drawbacks of each.  They will be involved in hypothesis generation and study design for projects that are at that stage.  For ongoing projects, they will learn about the informed consent process and be involved in screening for study subjects and subject selection and enrollment.  They will be allowed to consent for studies judged to be minimal risk.  Students will be taught important rules regarding data acquisition and entry, particularly as it relates to standards that have been set forth in the medical literature.  They will learn about bias and inter-rater reliability. Students will participate in data entry, data analysis, and subsequent abstract/manuscript preparation based on their level of interest and ability for time commitment.  Students will meet weekly with one of the course masters to discuss study progress and to identify any roadblocks to study completion.  These meetings will also serve as a forum for one on one education of the student regarding study methodology, ethical issues in research, and various resources available to the clinical researcher at Washington University.

Keith A. Hruska, MD
5th Floor McDonnell Pediatric Research Building
314-286-2772
Our laboratory’s focus is on two aspects of kidney diseases: the progression of chronic kidney disease (CKD), and the syndrome of the CKD-mineral bone disorder (CKD-MBD). The latter is an important cause of mortality associated with CKD. We have discovered the pathogenesis of the CKD-MBD in early stage 2 CKD. We have ongoing studies of CKD stimulated vascular calcification in which we have discovered the mechanism of atherosclerotic palque calcification stimulated by phosphorus. We are analyzing phosphorus as a cardiovascular risk factor, and new therapies for chronic kidney disease, the CKD-MBD, and vascular calcification.

Stuart A. Kornfeld, MD
8th Floor Clinical Sciences Research Building
314-362-8803
Synthesis, processing and sorting of glycoproteins, including lysosomal enzymes. Intracellular protein trafficking.

Sandor J. Kovacs, MD, PhD
9965 Clinical Sciences Research Building
314-362-8901
For students with math, physics and engineering background. Cardiovascular biophysics research elective concentrates on physiologic modeling and comparison of model predictions to in vivo human data. Minimum of eight weeks of elective time.

Jack Ladenson, PhD
314-454-8436
Development of monoclonal and single-chain antibodies for use in research and in diagnostic testing.

Marc S. Levin, MD, and Deborah C. Rubin, MD
922/924 Clinical Sciences Research Building
314-362-8933, 314-362-8935
Students will be members of a collaborative research team headed by Drs. Levin and Rubin (Department of Medicine) investigating the mechanisms underlying the intestinal adaptive response that occurs to compensate for loss of functional small intestine. A second project focuses on epithelial-mesenchymal interactions and their role in regulating gut epithelial proliferation carcinogenesis and the normal and cancer stem cell niche. Specific mechanisms under investigation include the function of an immediate early gene Tis7 on gut adaptation following resection or injury. The role of myofibroblast protein epimorphin in regulating cell proliferation and colon carcinogenesis is being explored. The student will have the opportunity to learn basic molecular biology and physiology as it relates to small intestinal growth, and function. Examples of techniques that are used in these studies include small animal surgery and colitis and cancer models (mice and rats), molecular biological techniques including PCR, Northern blotting, vector construction for production of transgenic and knockout mouse models, in situ hybridization and immunohistochemistry.

Philip W. Majerus, MD
8th Floor Clinical Sciences Research Building
314-362-8801
Biochemistry of platelets, regulation of lipid metabolism in tissue culture; mechanism of platelet thrombus formation.

Jeffrey D. Milbrandt, MD, PhD
101 Biotechnology Center
314-362-4650
We have several ongoing projects in our laboratory that focus on peripheral neuropathy and neurodegenerative diseases. (1) Using high throughput screening methods to dissect the molecular program responsible for dismantling injured and/orunhealthy axons with the goal of identifying drugs to treat neurological disorders. (2) Using genetics and metabolomics to understand how metabolic deficits in glia lead to neuropathy and axon breakdown. (3) Developing new genetic tools for in vivo and in vitro assays aimed at characterizing the role of non-myelinating Schwann cells in acquired peripheral neuropathies such as diabetic neuropathy. (4) Implementing novel, high-throughput genome engineering technologies in induced pluripotent stem cell-derived neurons to perform functional genomic screens for pathways involved in axon regeneration.

Jason C. Mills, MD, PhD
Room 1030 CSRB North Tower
314-362-4213
We investigate the differentiation of epithelial stem cells in the upper GI tract. We study how genes regulate differentiation in mouse models and in vitro in tissue culture, and we correlate our findings with human tissue specimens. Specific projects include: (1) understanding how inflammation leads to aberrant differentiation (metaplasia), which is a precursor for cancer; (2) elucidating how master regulatory transcription factors like Xbp1 and Mist1 coordinate the massive cytoskeletal and organellar expansion of specialized secretory cells as they differentiate from stem cells; and (3) understanding mechanisms regulating how differentiated cells can be reprogrammed into stem cells in GI organs like stomach and pancreas.

Stanley Misler, MD, PhD
815 Yalem Building, Barnes-Jewish Hospital
314-454-7719
Stimulus-secretion coupling in endocrine cells (B-islet cells and adrenal chromaffin cells) examined using single-cell assays of secretion (capacitance measurements, amperometery).

Ginger E. Nicol, MD
4412 Renard Building
314-362-5939
Clinical research concerning substrate (glucose and lipid) metabolism and the regulation of weight and body composition in persons with mental illness, particularly concerning the effect of psychotropic medications. This elective offers the student a broad exposure to clinical research protocols, including protocols in adults and children. Students will have an opportunity to focus on a particular project of interest.

Amit Noheria, MBBS, SM
Northwest Tower 13th Floor
314-249-7352
Clinical Outcomes in Patients with Cardiac Implantable Electronic Devices: Clinical research to evaluate outcomes in patients with cardiac implantable electronic devices (CIEDs).

  1. Risk of stroke in patients with patent foramen ovale and CIEDs.
  2. Predictors of hemodynamically unstable ventricular arrhythmias in patients with left ventricular assist devices (LVADs).

Richard E. Ostlund, MD
8804 Wohl Hospital
314-362-8286
Our laboratory focuses on the prevention and treatment of coronary heart disease by studying cholesterol absorption, detoxification and elimination from the body. Direct patient studies that use new stable isotopic cholesterol tracers and mass spectrometry techniques complement in vitro work on the biochemistry of cholesterol transport in cultured cells.

Russell Pachynski, MD
BJC Institute of Health, 7th Floor
314-286-2341
My lab focuses on several aspects of tumor immunology and translational immunotherapy. We utilize mouse tumor models, human tissues and samples, and advanced molecular and immunologic techniques to look study leukocyte trafficking in the setting of tumor development and progression. We also have projects focusing on developing novel immunotherapeutics aimed at augmenting the recruitment of beneficial leukocyte subsets into the tumor microenvironment in order to suppress tumor growth. We are utilizing several approaches such as nanoparticles, fusion proteins, and viruses.

Katherine Ponder, MD
8818 Cancer Science Research Building
314-362-5188, kponder@wustl.edu
Gene Therapy for Lysosomal Storage Diseases. Our laboratory is interested in using gene therapy to treat lysosomal storage diseases such as mucopolysaccharidosis (MPS). We have developed a retroviral vector that can be efficiently delivered to the liver of mice and dogs, and results in expression that is sufficient to reduce many of the clinical manifestations of these genetic diseases. Current studies focus upon assessing the therapeutic effect of gene therapy on sites that are affected in MPS such as the heart, aorta, bones, and joints, and developing vectors that might be translated into human patients.  In addition, we are evaluating the pathogenesis of disease in MPS, which appears to involve the upregulation of destructive proteases in the aorta and possibly other sites.  A better understanding of the pathogenesis of disease might result in additional therapies for MPS.

Clay F. Semenkovich, MD
8th floor, Southwest Tower
314-362-4454
Fatty acid metabolism and its role in atherosclerosis, diabetes, hypertension, and obesity. The modulation of respiratory uncoupling for the treatment of aging, obesity, and vascular disease.

Phyllis K. Stein, PhD
Room 13116 Northwest Tower
314-286-1350, pstein@dom.wustl.edu
Clinical Significance of Heart Rate Variability and ECG-Derived Waveform Parameters Obtained from Continuous Ambulatory Monitoring. This elective affords the opportunity to perform research in heart rate variability or in other measurements, like QT variability or T-wave alternans that can be derived from continuous ECG monitoring from Holter recordings or polysomnography recordings in the sleep lab. One area of active research is the identification of heart rate patterns associated with obstructive and central sleep apneas and hypopneas and the relationship of previously unappreciated cycling heart rate patterns and outcomes. Data are also available from mice. Many possible projects are available using our many large existing datasets, using the thousands of stored studies in the sleep lab or involving de novo data collection in a clinical or animal population and in infants. Also, many possible directions for this research are available from applying traditional and non-linear HRV to different populations, developing methods to quantify ultradian heart rate variability patterns, to developing novel ECG analysis techniques, etc. Also, we are involved with the Cardiovascular Health Study (CHS), a large population-based longitudinal study of risk factors for heart disease and stroke among community-dwelling people >65 years old. There is a subset of this population who had Holter recordings (~1400 at baseline, ~800 of the same people 5 years later, and ~370 minority subjects recorded at the same time as the second CHS recording). These recordings have already been analyzed by us so there is a large amount of heart rate variability and heart rate pattern data available. There is also a subsets of the CHS and of another study (EPHESUS) who are known to have died suddenly, and we have developed a matched control group in order to examine ECG-based differences in those who died suddenly. We also have electronic sleep studies at two time points for about 300 of the CHS Holter participants who also participated in the Sleep Heart Health Study. We have analyzed an additional ~1500 sleep studies from CHS participants who did not have Holter recordings. Thus, there is also an opportunity in the CHS dataset for studies on the relationship of heart rate variability and changes in heart rate variability over time and a huge number of clinical and demographic factors among the elderly. We also have data on the relationship of Holter-based HRV and sleep apnea patterns to the development of atrial fibrillation post-cardiac surgery and data from a study of treatment of depression in treatment-resistant depressed post-MI patients, a study of sickle cell patients and one of heart rate variability and echo parameters in elderly African Americans.  Currently we are also analyzing HRV in both premature infants as they mature and also HRV as a predictor of response to treatment in babies in the NICU and PICU, using stored 24-hour bedside ECGs.

Heart Rate Variability and Clinical Outcomes: The student will be learning about HRV Methods and will investigate the relationship of HRV and outcomes in one of our datasets. Because we have clinical and demographic data on about 20,000 people in who continuous ECGs from Holter recordings, sleep studies and ICU studies and also some mouse data, the student will be able to choose a project leading to a publishable result in an area of interest to the student. The HRV Lab has enough computers and software to accommodate the needs of any interested students.

John Turk, MD, PhD
8th Floor South West Tower
314-362-8190

Phospholipid signaling mechanisms in pancreatic islets. Experience in mass spectrometric analysis of complex lipids is available.

H.J. Wedner, MD
5002 Steinberg Pavilion, Barnes-Jewish Hospital, North Campus
314-454-7937 or 314-454-7377

  1. Asthma Care in the Inner City: students will participate in ongoing studies of the delivery of asthma care to inner-city children and adults. The emphasis will be on direct contact between the asthmatic patients and the student, along with an asthma counselor.
  2. Biology of Pollen and Fungal Allergens: our laboratory has been characterizing the important allergenic proteins from molds and pollen. The allergens are identified using skin test sensitive individuals, and the proteins are isolated and characterized by a combination of physiochemical and molecular biological techniques. These studies should lead to better forms of allergy immunotherapy. Students will participate in the isolation, characterization and modification of major allergens from a number of molds including Stachybotrysatra, Epicoccum nigrum and several pollens including those from white oak and Parthenium hysterophoros,a newly recognized allergen.