The laboratory is interested in characterizing mechanisms important in the control of cerebral hemodynamics under physiologic and pathologic conditions such as traumatic brain injury and cerebral hypoxia/ischemia, particularly in the perinatal period, using a basic science piglet model. Current research interests focus on tPA, its role in the physiologic and pathologic control of cerebral hemodynamics, and its potential clinical utility in the treatment of central nervous system disorders.
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In spite of substantial research concerning the abnormalities in carbohydrate metabolism that define diabetes mellitus, relatively little attention has gone to the lipid abnormalities. This is somewhat surprising given the intimate relationship of dyslipidemias with cardiovascular disease, the major source of morbidity and mortality in diabetes. My lab studies the normal metabolic and regulatory pathways that govern lipid synthesis, transport and utilization in mice and in the fruit fly, Drosophila melanogaster. In both species, there appear to be at least three pathways which regulate, for example, lipogenesis: insulin, whose secretion is governed by circulating nutrients; ChREBP, a transcription factor positively regulated by glucose; and AMPK, a protein kinase activated by nutrient stress. Projects are underway studying each of these pathways, ultimately to determine if any account for lipid abnormalities in Type 2 diabetes mellitus.
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Betsy Goldmuntz, MD is a pediatric cardiologist who studies the genetic basis of congenital heart disease.
Current projects in this research group include:
- Genome wide analyses of large patient populations to identify genetic risk factors for disease
- Mutation and SNP studies of candidate genes
- Translational studies on the impact of genotype on clinical outcome.
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We run a large patient-oriented research program with ongoing projects involving risk stratification of patients with potential acute coronary syndromes, including:
- Development of novel markers of acute coronary syndromes
- Evaluation of different diagnostic tests for 30-day risk stratification of these patients, including CT coronary angiography and serum markers
- Cost effectiveness evaluation of different risk stratification strategies in the ED and observation unit
- Quality assurance projects evaluating different aspects of traditional care of these patients
We have a data base with over 7000 patient already enrolled in a variety of studies at HUP and access to multicenter databases with over 20,000 additional patients in ACS and HF studies. You will design your own specific research question, complete a more thorough and directed literature review. Using the knowledge gained from this review along with your experience in the above studies, you should prepare a well thought out research proposal including a Background, Specific Aims, Summary of Preliminary Studies and Research Methodology. We will provide assistance with Statistical Design.
If your study proposal required additional data be collected prospectively, we will adapt our data collection instruments and obtain the required data. You will need to complete a manuscript during the 3 month period that will be submitted for publication. You will be the first author. Judd Hollander, MD will meet with you, as needed, on a daily basis to discuss your progress and participation.
This is opportunity for the resident to develop their own study question and submit a first author manuscript within a 3 month time period.
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Our group is focused on improving patients' medication response through a better understanding of, and interventions to improve, adherence and through quantifying the effects of genetic variants on medication response.
Extensive database on warfarin treated patients, including clinical, adherence, and genetic data. Clinical trial database on hypertensive patients, which can be used to understand predictors of response to drugs, response to interventions to improve adherence.
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The Krymskaya Lab is investigating signaling mechanisms of vascular smooth muscle remodeling under chronic hypoxia as it relates to the pathobiology of PAH and COPD. M.D.'s with interest in pulmonary biomedical and translational research are welcome to participate in my research projects. Initial 2-3 month work in an interactive group in this lab will provide an introductory experience in signal transduction, cell biology, confocal microscopy and use of genetically engineered mice. Successful participation in specific research project during residency training may culminates in co-authorship in scientific publications.
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The Poncz Lab focuses on issues related to platelet biology andthrombus development. Projects range from looking at the regulated expression of megakaryocyte-specific genes, the biology of several platelet-specific chemokines mostly in animal models, the molecular basis of heparin-induced thrombocytopenia and the biology of platelet integrin receptors. We also have several interesting models for the ectopic delivery of proteins to sites of thrombosis/inflammation via platelets. A variety of basic cell and molecular laboratory techniques, mouse models, and clinical research approaches are used in addressing these questions.
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Project One Description
In our Center for Hereditary Hemorrhagic Telangiectasia, the preferred approach to screening for the presence of pulmonary arteriovenous malformations is a contrast echocardiogram ('bubble study'). Those found to be positive for late passage (ie, contrast appearing in the left atrium 4-10 beats after appearance on the right side), undergo high-resolution CTA of the lungs. We are interested in quantifying the findings on the echocardiogram and correlating these data with the findings on CT and on subsequent pulmonary angiography if the patient is deemed to have lesions needing embolization. This project will be a collaboration among the echocardiography faculty, Dr. Scott Trerotola in Interventional Radiology and myself.
Project Two Description
We have demonstrated recently in patients with hereditary hemorrhagic telangiectasia (HHT) that transillumination of the fingers can detect arteriovenous and other vascular malformations that are not visible on examining the skin. Further, such defects correlate with increased blood flow as shown by Doppler. We now want to extend these studies to include a systematic survey of patients with, and suspected as having, HHT as they present to our Center (typically, we see 2-4 new patients each week). Furthermore, we have detected similar digital vascular anomalies in patients with aneurysm of the aorta, and plan to survey such subjects systematically as well. Typically we evaluate 4-6 such patients weekly.
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The following list of (8) Clinical and Translational Research Studies is sorted into two categories: (A) Observational / Cohort Studies, and (B) Experimental Studies. Dr. Muredach Reilly acts as the single contact for each study.
A. OBSERVATIONAL / COHORT STUDIES
- Genetics of Atherosclerosis in Chronic Kidney Disease (Gen-CRIC)
Gen-CRIC (Chronic Renal Insufficiency Cohort) is a candidate gene/pathway human genetic study of inflammatory, metabolic, and cardiovascular (CVD) outcomes in the NIH-sponsored multi-center CRIC study (cohort study of CVD and renal outcomes) in patients with mild-moderate chronic kidney disease (CKD). Cohort recruitment will be complete fall 2006 and genotyping will proceed in 2007 with analyses of cross-sectional outcomes [biomarkers and coronary artery calcification (CAC)] in 2007 to 2008 and longitudinal outcomes (individual and composite of hard clinical CVD events) from 2009 to 2011.
- Penn Diabetes Heart Study (PDHS)
The Penn Diabetes Heart Study is a study of genetic and biochemical factors related to the development of atherosclerosis in persons with type II diabetes. Approximately 1000 subjects have been enrolled to date with a goal of enrolling 2000 by the end of 2008. Subjects undergo a number of tests including ABI, heart rate variability, EKG and coronary artery calcification (CAC) by EBT. In fall 2006, we start examining a number of candidate biochemical and genetic risk factors for atherosclerosis in the first 1000 participants.
Persons undergoing cardiac catheterization at either HUP or Presby are consented for the Cath study to identify genetic and biochemical factors related coronary disease. More than 3800 subjects have been enrolled to date (began in 1998) from this have a subset of closely matched cases and controls as well as subjects with acute coronary syndrome (approximately 800).
- Study of Inherited Risk of Atherosclerosis (SIRCA)
The Study of the Inherited Risk for Coronary Atherosclerosis (SIRCA) is a cohort study of approximately 900 singletons as well as 440 people that are part of 150 sibships. Subjects were recruited based on having a family history of CAD but few other traditional risk factors for heart disease. At the study visit they had several physical measurements, coronary artery calcification measurement by EBT and fasting lipids (blood and DNA saved for measurement of genetic and biomarkers). Currently recruiting additional subjects (approximately 500) and working analysis of initial cohort. Have identified several biomarkers and SNPs related to CAC and are analyzing results from a genome wide scan.
B. EXPERIMENTAL STUDIES
- Inflammation and the Metabolic Syndrome (LPS-RO1)
This NIH-RO1 sponsored study examines the inflammatory response after LPS injection in normal subjects compared to subjects with the metabolic syndrome. We have enrolled 40 normal volunteers in the first phase of this project. We are currently focused on recruiting subjects with the metabolic syndrome.
- A Pilot Study of Metabolic Effects of Low-Dose Endotoxemia
This study examines very low dose human endotoxemia as a model for low-grade inflammation induced insulin resistance and atherogenic dyslipidemia in humans. This pilot is currently enrolling and will be complete by December 2006.
- Genetics of Atherogenic Responses to Low Dose Endotoxemia
This NIH-SCCOR sponsored translational study will recruit 300 subjects to examine the genetic predictors of gene expression, proteomic and metabolic atherogenic responses to very low dose endotoxemia in humans. This GCRC protocol forms part of a large integrated SCCOR project with Dr Rader – where the same subjects will be studies for the genetic predictors of the lipoprotein and metabolic responses to niacin therapy. This study will commence in January 2007.
- Carotid Atherosclerosis Regression and Magnetic Resonance Assessment (CARMA)
The purpose of this is study is to assess the effects of low dose (20mg) simvastatin, low dose simvastatin + niaspan vs. high dose simvastatin (80 mg) on carotid plaque morphology over 1 year as assessed by MRI in patients with known carotid disease and LDL > 100. Enrollment is We wish to enroll 69 subjects and have thus far enrolled 54.
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We currently welcome students for three projects:
The physiology of cardiac and ventilatory reserve capacity in health and inherited muscle disease
Translational research: Gene therapy for Duchenne Muscular Dystrophy
Physical Fitness in Recently Returning Combat Veterans
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Structure and function of ADAMTS13 metalloprotease
Cofactor dependent regulation of ADAMTS13 function
Characterization of autoantibodies against ADAMTS13 in patients with thrombotic thrombocytopenic purpura (TTP)
Gene therapy correcting ADAMTS13 deficiency in mouse models.
In vivo (animal) thrombosis models.
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