Thomas Jefferson University
Sidney Kimmel Medical College
Department of Medicine

Research Activity

Overview

From Research to the Power to Cure

The Center for Translational Medicine at Thomas Jefferson University is primarily focused on bridging cutting-edge basic research with clinical medicine in order to more efficiently translate new discoveries at the bench to the realization of improved patient care.

Our center, which is at the forefront of academic medicine, creates a new culture of collaboration and cooperation, merging a world-class team of basic science investigators with Thomas Jefferson University and Hospital’s renowned physicians and clinical investigators.

The Center for Translational Medicine conducts broad and multi-focal research. Multiple labs are engaged in models of heart and vasculature disease. Our research focuses on the regulation and signaling of many molecules vital in the progression in heart muscle diseases utilizing novel genetically engineered mouse models or viral-mediated myocardial gene delivery. We also study cellular and molecular mechanisms of cardiovascular development in vertebrates (Astrof Lab).

Pulmonary research is another strength of the Center for Translational Medicine, fostered by collaboration with the Jane and Leonard Korman Lung Center. Understanding the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD), and developing novel drugs for their treatment, is the focus of the Penn Lab and Deshpande lab. The Deshpande Lab also investigates the mechanisms by which lung function declines with aging. Fibrotic lung disease, and the role of obesity in asthma, are the focus of the Summer lab. The Chan lab explores novel means of manipulating Akt kinase activity as treatment for multiple lung diseases.

Targeting mechanisms affecting bone and cartilage metabolism, as a means of treating or preventing osteoporosis and osteoarthritis, is the focus of the Wang lab.

Finally, our Center is also leading research in viral vector development and small animal models of disease.  The Small Animal Physiology Core is headed by Nadan Wang.

Our Current Areas of Interest

Mitochondria, Cellular Receptors, Kinases and Cell Adhesion Proteins

Diseases of the Vasculature Focus on the Role of Platelets, Proteases, Nuclear Receptors, and Reactive Oxygen Species Signaling in Human Diseases

Cellular & Molecular Mechanism of Cardiovascular Development in Vertebrates

Pulmonary Research

Skeletal Biology and Diseases

Obstruction and Bladder Disease

Funded Projects - Past & Present

Dr. Sophie Astrof

Current Support

NIH, R01 HL103920 (PI)
07/2010 - 06/2016
“Role of integrin α5 in the development of the aortic arch arteries”

“Cell-ECM interactions in the development of the aortic arch arteries” (PI)
This is the competitive renewal of my current R01 grant. This grant was scored within the funded NHLBI percentile and is projected to start in June 2016.

AHA, Grant-in-Aid (PI)
01/2016 – 12/2017
“Role of fibronectin in development of the cardiac neural crest”

Completed Support

The Weizmann Institute of Science -Thomas Jefferson University Collaboration
Program (Co-PI)
07/2013 – 06/2014
“Genetic Regulation of Neural Crest Development”

AHA, National Innovative Grant Research (PI)
01/2012 – 12/2013
“Identification of a novel evolutionarily conserved element regulating the cardiac neural crest”

AHA, Scientist Development Grant (PI)
07/2008 – 06/2012
“Role of EIIIA and EIIIB splice variants of fibronectin in the development of aortic vascular smooth muscle cells”

The W. W. Smith Charitable Trust (PI)
01/2011 – 12/2011
“Function of integrin alpha 5 in cardiac development and disease”

Dr. Tung Chan

Current Support

Dean’s Transformational Science Award (PI)
06/2015 - 6/2017
“Development of Akt Kinase Directed Small Molecules Targeting a Novel Allosteric Regulatory Switch”

Goals: Re-constituting Akt "dephosphorylation-protection cage" in a bacteria expression system and to exploit structural and mechanistic insights into "dephosphorylation-protection cage" to enable rational design of superior small molecule regulators of Akt.

AHA, Grant-In-Aid (PI)
07/2014 - 06/2016
“Dephosphorylation Regulation by Akt Carboxy-Terminus and a Novel Lipid-Bridge for Selective Akt2 Activator Development”

Goals: Developing specific carboxyl-terminal-targeting peptides and peptidomimetics that will selectively protect Akt2 against dephosphorylation, using both cell-free and cell-based assays.

ALA, Biomedical Research (PI)
07/2014 - 06/2016
“Lung Pathology Therapies Based on Akt Dephosphorylation Regulation”

Goals: This grant focuses on characterizing how manipulating bridging interactions in the hydrophobic pocket of Akt can protect Akt against dephosphorylation and thereby increase Akt activity in lung alveolar cells.

NIH/NHLBI, R01 HL58506 (Co-I)
02/2013 - 01/2018
“G protein-coupled receptor signaling in airway smooth muscle”

Goals: Specific Aims focus on characterizing mechanisms the effector and regulatory feedback mechanisms of GPCR-mediated PKA activity in airway smooth muscle.

NIH, P01 HL114471-01 (Co-I)
07/2013 - 06/2018
“Novel Molecular Mechanisms promote GPCR-induced bronchodilation in asthma”, Project 4 “Function and Targeting of the Proton-Sensing GPCR OGR1 in ASM

Goals: To characterize pH-, and novel small molecule ligand-, mediated regulation and function of OGR1 in airway smooth muscle.

Dr. Jason Choi

Current Support

NIH/NHLBI, R00 HL118163 (PI)
02/2016 – 01/2019
“Dusp4 in the pathogenesis of LMNA cardiomyopathy”

Dilated cardiomyopathy arising from mutations in the LMNA gene is a highly deadly disease with little understanding of the pathogenic mechanisms involved. We identified Dusp4 as a mediator of LMNA cardiomyopathy and this project aims to elucidate its role in the disease pathogenesis. As no specific treatment currently exists to treat LMNA cardiomyopathy, understanding the molecular mechanisms involved will lead to novel mechanism-based therapies to treat LMNA cardiomyopathy and perhaps, other forms of cardiomyopathy. The proposed aims will take a multidisciplinary approach, spanning molecular and biochemical analyses to in vivo mouse genetics and live animal studies, with the ultimate goal of rapidly translating the gained knowledge into new clinical practice.

Completed Support

NIH/NHLBI, F32 HL094037 (PI)
02/2010 – 01/2013
“Molecular and Cellular Pathogenesis of Emery-Dreifuss Muscular Dystrophy”

Dr. Deepak A. Deshpande

Current Support

NIH/NIA, R01 AG041265 (PI)
07/2012 – 06/2017
“Molecular basis of age-dependent changes in airway smooth muscle functions”

NIH/NHLBI, R01 HL104119 (PI)
05/2013 – 04/2015
“Novel mechanisms of smooth muscle Beta2-receptor regulation relevant to asthma”

American Asthma Foundation, AAF 13-0063 (PI)
07/2013 – 06/2016
“Anti-mitogenic effect of bitter taste receptor agonists on airway smooth muscle”

Completed Support

NIH/NHLBI, K99/R00 HL87560 (PI)
12/2006 – 11/2012
“Molecular Mechanism of airway smooth muscle relaxation” 

Dr. Boopathi Ettickan

Completed Support

University of Pennsylvania, O’Brien Urology Research Program (PI)
2007 - 2008
“Role of stretch in transcriptional regulation of desmin and Vimentin gene expression in smooth muscle”

University of Pennsylvania, ARRA funded O’Brien Urology Research Program (PI)
2009 - 2011
“Role of hypoxia in transcriptional regulation of desmin and Vimentin gene expression in smooth muscle”

Dr. Raymond Penn

Current Support

NIH/NIAID, R01 AI110007 (PI)
 07/2014 – 06/2019
“Optimizing beta-adrenoceptor signaling bias in asthma”

Goals: Identify therapeutic and pathological signaling via the beta-2-adrenoceptor in models of asthma.

NIH/NHLBI, P01 HL114471
07/2013-06/2018
Project 4 "Function and Targeting of the Proton-Sensing GPCR OGR1 in ASM" (Penn, PI) of PO1 "Novel Molecular Mechanisms Promote GPCR-Induced Bronchodilation in Asthma" (Panettieri, PI)

Goals: Characterize OGR1 signaling, function, and regulation in human airway smooth muscle cells in vitro, ex vivo, and in vivo, elicited by reduced extracellular pH and novel ligands.

NIH/NHLBI, RO1 HL58506 (PI)
02/2013 – 01/2018
"G protein-coupled receptor signaling in airway smooth muscle"

Goals: Specific Aims focus on characterizing mechanisms the effector and regulatory feedback mechanisms of GPCR-mediated PKA activity in airway smooth muscle.

Dr. Glenn Radice

Current Support

NIH/NHLBI, R56 HL125988-01 (PI)
09/2015 - 08/2016
“Alpha-Catenins in Mechanochemical Signaling”

This R56 application investigates the role of a-catenins in regulating cytoskeletal tension and Yap activity in the heart.

NIH/NCI, R21 CA176097-01A1 (PI)
12/2013 - 11/2016
“N-cadherin and Metastatic Dissemination”

This R21 application investigates the fate of N-cadherin-deficient tumor cells in a mouse model of pancreatic cancer using a lineage tracing method.

Dr. Khadija Rafiq

Current Support

NIH, R01 (PI)
07/2013 - 06/2018
“Inflammatory proteases and Diabetic Cardiomyopathy”

The research proposed in this application will delineate the role of inflammatory proteases in mediating alterations in insulin/insulin growth factor-1 receptor signaling and determine their involvement in the development of diabetic cardiomyopathy

Completed Support

AHA, 0730109N (PI)
01/2007 – 12/2010
“Role of Ubiquitin Proteasome System in Cardiac Myocytes Apoptosis Induced By Inflammatory Proteases”

The research proposed in this application aimed to delineate the role of ubiquitin proteasome system activation in cardiac myocyte death induced by inflammatory proteases.

Dr. Shey-Shing Sheu

Current Support

NIH/NHLBI, 1R01HL122124 (Co-PI)
02/2014 - 1/2018
“Mitochondria-SR Tethering: Its Role in Cardiac Bioenergetics and Ca2+ Dynamics”

We will apply interdisciplinary approaches to test the hypothesis that mitochondria and sarcoplasmic reticulum tethering via Mfn2 family proteins creates a micro-domain of high Ca2+ between these two organelles during excitation-contraction coupling. Moreover, mitochondria Ca2+ uniporters are clustered in the region of inner mitochondrial membrane that is in proximity with SR. Losses of this juxtaposition decrease excitation-bioenergetics coupling efficiency that leads to energy deficiency and oxidative stress and subsequent heart failure.

NIH/NHLBI, 2R01HL093671 (PI)
07/2014 - 04/2018
“Ca2+ and ROS Crosstalk Signaling in Cardiac Mitochondria”

This project is to establish a unified theory to describe the mechanisms of crosstalk signaling between Ca2+ and reactive oxygen species (ROS) in cardiac muscle cells, and to translate these signaling pathways to the physiology and pathology of cardiac excitation, contraction, and energy metabolism.

NIH/NHLBI, 1R01HL114760 (Co-I),
08/2012 - 04/2017
“Mitochondrial Respiration and Superoxide Production in Healthy and Failing Heart”

There are three specific aims in this proposal:
1. Test the hypothesis that superoxide flash arises from the transient acceleration of mitochondrial respiration and is modulated by mitochondrial Ca2+, permeability transition pores and fission/fusion dynamics.

2. Test the hypothesis that pathological stress inhibits superoxide flash activity at an early stage of heart failure and prior to detection of overt signs of mitochondrial dysfunction.

3. Determine whether increased mitochondrial or cytosolic ROS contributes to oxidative stress during mitochondrial respiratory dysfunction.

Completed Support

NIH/NHLBI, R21 HL110371 (PI)
07/2011 – 06/2013
“ADP: A Master Regulator for Bioenergetics and Ca2+/ROS Signaling in Heart”

NIH/NHLBI, 5R01HL033333 (PI)
04/2006 – 09/2012, no-cost extension
“Mitochondrial Ca2+ Transport in Heart Cells”

Dr. Ross Summer

Current Support

NIH/NHLBI, RO1 HL105490 (PI)
07/2011 - 06/2016
“Adiponectin inhibits activation and injury of lung endothelium”

NIH, R21 AA023571 (PI)
06/2015 - 07/2017
“Alcohol –Induced Lung Lipid Changes Contribute to development of Acute Lung Injury”

Completed Support

NIH/NHLBI R21 HL112672 (Co-I)
04/2012 - 03/2014
“Adiponectin in acute lung injury”

NIH/NHLBI K08 HL077138 (PI)
04/2006 - 03/2011
“The Identification and Study of a Lung Mesenchymal Stem Cell”

Dr. Jianxin Sun

Current Support

NIH, R01 HL103869-01 (PI)
11/2010 - 11/2016, no cost extension
“Regulation of Endothelial Nitric Oxide Synthase mRNA Stability”

The main goal of this project is to elucidate the molecular mechanisms regulating endothelial nitric oxide synthase expression at post-transcriptional levels

AHA, Established Investigator Award (PI)
01/2016 - 12/2020
“Role of PCMT1 in Cardiac Ageing”

The main goal of this project is to elucidate the anti-aging effect of PCMT1 in the heart and its mechanism of action.

Completed Support

AHA, SDG 0630047N (PI)
01/2006 - 12/2009
“Post-transcriptional Regulation of Endothelial Nitric Oxide Synthase Expression”

The main goal of this project is to identify the proteins that regulate endothelial nitric oxide synthase expression at post-transcriptional levels.

Dr. Bin Wang

Current Support

NIH/NIAMS, R03 AR063289 (PI)
04/2013 - 03/2016
“Novel Regulation of PTH Receptor Functions in Bone”

NIH/NIAMS, R03 AR062705 (PI)
07/2013 - 06/2016
“Novel Mechanism of PTH Effects on Bone Metabolism”

CTM Seminar Series

2015-2016

October 19, 2015 - William Thomas Gerthoffer, Ph.D.

"MicroRNA based therapy of asthma and pulmonary hypertension"

December 3, 2015  - Xin L. Ma, Ph.D.

      "Adipocyte Endocrine Dysfunction and Diabetic Cardiovascular Disease"

December 17, 2015 – Jin Ouchi, M.D., Ph.D.

      "Molecular and functional regulation of mitochondrial calcium uptake"

January 7, 2016 – Glenn Radice, Ph.D.

     "Alpha-catenins as regulators of cytoskeletal architecture and cardiac regeneration"

January 21, 2016 – Jianxin Sun, Ph.D.

      "Nur77: Orphaned at Birth but Adopted by Cardiovascular Pathophysiology"

February 11, 2016 – Ross Summer, M.D.

      "Obesity primes the lung endothelium to injury"

March 31, 2016 – Bradley J. Davidson, Ph.D.

      "Mitotic membrane turnover: re-writing cell fate decisions during division"

April 7, 2016 – Sophie Astrof, Ph.D.

      "Cell-extracellular matrix interactions in cardiovascular development and smooth muscle differentiation"

April 21, 2016 – Bin Wang, Ph.D.

      "Mechanism of parathyroid hormone effect on bone"

May 5, 2016 – Boopathi Ettickan, Ph.D.

      "A tale of three proteins: GATA-6, NFkB and desmin, friends or foes for muscle and mitochondrial physiology "

May 17, 2016 - Wang Wang, Ph.D.

May 26, 2016 - Luisa Iruela-Arispe, Ph.D.

June 2, 2016 - Khadija Rafiq, M.D. Ph.D

October 20, 2016 - Kenneth Walsh, Ph.D