Cardiovascular Research at Penn
Building Bridges, Accelerating Discovery, Advancing Care
The Penn Cardiovascular Institute bridges the expertise of scientists and clinicians across the Penn Campus and Health System
to generate discoveries targeted to treat and cure heart and vascular disease. The Penn CVI is organized into
six research programs bridging basic science and clinical investigation to better promote
interdisciplinary research.
| Current Research Projects: |
Genomics of Myocardial Transcription Factors in Cardiac Remodeling
Sponsor: NIH, Grant # R01HL088577,
PI: Thomas P. Cappola »
Cardiac remodeling is a central feature of human heart failure and shows substantial variation in human subjects.
A decade of research in murine models and research in humans performed by the
Principal Investigator show that a discreet set of cardiac transcription factors integrate stress signals to cause cardiac remodeling.
Our central hypothesis is that common genetic variation in a core set of cardiac transcription factors (MEF2, NKX, NFAT, GATA, FOX)
is in large part responsible for the variable course of cardiac remodeling in humans. We will address this hypothesis by performing
SNP- and haplotype-based association studies of candidate transcription factors in two existing cohort studies that capture the common phenotypes
of remodeling encountered in clinical practice. Aim 1 tests the hypothesis that variation in
candidate transcription factors is associated with concentric cardiac remodeling in the
Chronic Renal Insufficiency Cohort study (CRIC), a large cohort with a high prevalence of concentric remodeling. Aim 2 similar analyses is performed in the Penn Heart Failure Study, a large single-center cohort initiated by the applicant with a high prevalence of eccentric remodeling. In Aim 3 we collaborate with Dr. Edward Morrisey, an expert molecular biologist, to determine the mechanisms by which the observed risk variants alter transcription factor function using in vitro techniques. |
Genetic Determinants of Hypertensive Heart Disease in Chronic Renal Insufficiency
Sponsor: NIH, Grant # R01HL091663, PI: Daniel L. Dries »
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with chromic renal insufficiency (CRI).
CVD remains the leading cause of death in dialysis patients and in patients undergoing renal transplantation. There is accumulating evidence that the increase in CVD burden is present in the pre-dialysis population.
Left-ventricular hypertrophy (LVH) is perhaps the best studied marker of CVD in the chronic kidney disease (CKD) population.
The central hypothesis of this project is that genetic variation in corin and related NPS pathway genes contributes to the progression of hypertensive heart disease in the setting of
chronic renal insufficiency (CRI). The candidate genes of interest are: corin, furin, ANP, BNP, CNP, NPR-A, NPR-B, NPR-C, PKG-I, and NEP.
We will test these hypotheses in the Chronic Renal Insufficiency Cohort (CRIC):
an NIH-sponsored, multi-center, prospective cohort study of cardiovascular disease in subjects (N=3000) with chronic renal insufficiency. |
Analysis of a Novel Homeobox Gene in Cardiovascular Development
Sponsor: NIH, Grant # R01HL071546, PI: Jonathan A. Epstein »
Initial research focused on the role of a novel homeodomain protein called Hop that we discovered in the embryonic heart.
We have found that Hop loss of function results in a developmental cardiac defect and that over-expression results in cardiac hypertrophy.
Hop can function at the molecular level as a transcriptional co-repressor by recruiting class I HDACs. This finding led us to test the effects of HDAC inhibitors
and we have found that these agents can block cardiac hypertrophy induced by Hop over-expression and also hypertrophy resulting from other stresses
including beta-adrenergic agonists and stretch. Therefore, we have sought the specific class I HDAC(s) that account for these effects, and we have
identified high levels of HDAC2 in the developing and adult heart. HDAC2 loss of function results in mice that are resistant to Hop- induced cardiac
hypertrophy and to hypertrophy induced by beta-adrenergic agonists. |
Pax3 Regulation of Cardiac Conotruncal Development
Sponsor: NIH, Grant # R01HL061475, PI: Jonathan A. Epstein »
Neural crest plays important roles in cardiovascular development since derivatives contribute to the outflow tract of the heart and to the great vessels. Mutations in neural crest genes, including Pax3,
lead to congenital heart disease. This competitive renewal application builds upon significant data and resources that we have developed during the first granting cycle in order to elucidate the molecular pathways
responsible for regulating Pax3 expression in neural crest. |
Neurofibromin, Neural Crest and Cardiac Development
Sponsor: NIH, Grant # R01HL062974, PI: Jonathan A. Epstein »
A project focusing on the role of the Nf1 gene product neurofibromin during cardiac development. In humans, NF1 is mutated in patient with von Recklinghausen Neurofibromatosis, a disease characterized by
benign and malignant tumors of neural crest origin. Nf1 knockout mice display enlarged endocardial cushions and succumb during mid-gestation with evidence of cardiovascular impairment.
The cardiac defects include pulmonic stenosis, double outlet right ventricle and thinned myocardium, defects that are seen in other mouse and chick models of cardiac neural crest-related congenital heart disease.
However, our recent studies demonstrate that neural crest migration and patterning in the heart is normal in Nf1-deficient embryos. |
Molecular Basis of Vascular Heterogenity and Function
Sponsor: NIH, Grant # P01HL075215, PI: Jonathan A. Epstein »
The overall goal of this program project proposal is to elucidate the signaling and transcriptional pathways involved in specifying unique functions of sub-populations of vascular smooth muscle and endothelial cells.
Recent molecular data confirms prior clinical observations that different parts of the vasculature are inherently distinct. For instance, pulmonary vascular smooth muscle and arterial smooth muscle react differently to
disease states and pharmacological intervention. Even within the arterial tree, smooth muscle arises from distinct precursors variably affecting congenital vascular disorders.
Vascular and lymphatic endothelial cells are specified in such a way as to express distinct molecular markers and adopt divergent functions.
Despite these observations, little is known about how these distinctions are orchestrated or how they contribute to functional differences within the vasculature.
The overlapping approaches and techniques used in this program will be relevant for understanding congenital and acquired vascular disease and for development of interventions
that target specific populations of vascular cells. |
Regulation of vascular development and function by LKLF
Sponsor: NIH, Grant # R01HL081654, PI: Mark L. Kahn »
During vascular development a primitive vascular plexus differentiates into a diverse network of arteries, veins and capillaries. Concurrent with vascular differentiation is the onset of circulating blood pumped by the heart and
the generation of hemodynamic forces that vary with vessel type. Although these processes are temporally linked, the extent to which vascular differentiation and genetic responses to hemodynamic forces are connected is unknown.
Lung Kruppel-Like Factor (LKLF, KLF2) is a transcription factor required for cardiovascular development. LKLF mRNA expression in endothelial cells is rapidly induced by pulsatile shear stress and during development and in adult life
LKLF is expressed in endothelial cells in proportion to their predicted exposure to fluid shear forces. Although LKLF expression is restricted to the endothelium, LKLF-deficient animals experience non-endothelial cardiovascular defects.
Understanding the mechanism by which LKLF regulates genetic responses in the developing and mature vasculature is expected to provide new insights into the pathogenesis and treatment of human vascular diseases. |
Role of SYK in Lymphatic Vascular Development
Sponsor: NIH, Grant # P01HL075215, PI: Mark L. Kahn »
We have recently identified a novel signaling pathway containing the tyrosine kinase Syk and the adaptor SLP-76 that is required for separation of blood and lymphatic vessels during lymphatic vascular development.
Loss of this signaling pathway in mice results in blood-filled lymphatics and the creation of arterio-venous shunts mediated by aberrant lymphatic connections.
How Syk signaling regulates separation of blood and lymphatic vessels is unknown and is the focus of this proposal.
During lymphatic vascular development Syk is expressed exclusively in hematopoietic cells and reconstitution of lethally irradiated wild-type mice with Syk-deficient fetal liver is sufficient to confer the vascular phenotype,
suggesting that Syk signaling may influence vascular development indirectly through circulating cells.
These studies will determine if Syk signaling defines a pathway required by hematopoietic progenitors
to contribute to vascular development in the embryo and vascular repair in the adult. Identification of such a pathway has broad implications for our understanding of vascular development and for
angiogenic therapies utilizing hematopioetic endothelial precursors. |
Regulation of Angiogenesis by SLP-76 Signaling
Sponsor: NIH, Grant # R01HL072798, PI: Mark L. Kahn »
Vascular development consists of two phases: vasculogenic creation of vessels by endothelial progenitor cells and subsequent angiogenic remodeling of existing vessels.
Mice lacking the hematopoietic signaling protein Slp-76 develop a vascular phenotype in which nascent lymphatic vessels connect to preexisting blood vessels.
Our studies of the cell type responsible for this vascular phenotype suggest that Slp-76 is required in hematopoietic endothelial progenitor cells and not in mature endothelial cells.
Remarkably, blood-lymphatic connections are corrected during later lymphatic remodeling, leaving surviving animals with arterio-venous shunts in which mesenteric lymphatics carry blood.
These congenital lymphatics subsequently lose lymphatic identity, suggesting that fluid flow forces are sufficient for the molecular reprogramming of lymphatic vessel identity in vivo. |
LKLF and Vascular Responses to Hemodynamic Shear In Vivo
Sponsor: NIH, Grant # K08HL081084, PI: John Lee »
A 5-year research and training program designed to investigate how the vascular endothelium senses the local hemodynamic environment and mediates an adaptive or pathologic response.
Clinical studies show that atherosclerotic lesions tend to develop in regions of the vasculature exposed to turbulent (low shear) blood flow. Regions of high shear tend to be protected.
Elucidating how local hemodynamic conditions effect vascular biological responses may lead to important advances in the treatment and prevention of vascular diseases, such as, atherosclerosis.
The central hypothesis is that a recently discovered shear-responsive transcription factor, LKLF, plays a critical role in modulating the vascular response to hemodynamic shear.
The training program will be supervised by Dr. Mark L. Kahn, in the Molecular Cardiology Research Center (MCRC).
The MCRC offers extensive collaborative opportunities, core facilities, and intellectual expertise in nearly all aspects of vascular biology.
Atherosclerosis studies will be performed in collaboration with Dr. Daniel S. Rader, an international leader in the field of lipid biology and pathogenesis of atherosclerosis. |
Regulation of Airway Morphogenesis and Differentiation by Wnt Signaling
Sponsor: NIH, Grant # R01HL087825, PI: Edward E. Morrisey »
The lung airways form through a reiterative process of branching morphogenesis with concomitant cellular differentiation that is regulated, in part, through the activity of multiple signal transduction pathways.
Accumulating evidence points to a role for both positive and negative signals from these pathways, which are regulated in a spatial and temporal manner during lung morphogenesis.
The action of these pathways results in the distinct proximal-distal patterning observed in the lung airways, which is essential for the proper differentiation of airway epithelia into the active
gas exchange interface in mammals. We have recently demonstrated a critical role for the Wnt signaling pathway in lung airway development and differentiation.
Our studies show that inactivation of Wnt7b results in severe lung hypoplasia resulting from inhibited airway branching as well as defects in mesenchymal proliferation and type I cell differentiation. |
Myocardin and Vascular Smooth Muscle
Sponsor: NIH, Grant # P01HL075215, PI: Michael Parmacek »
The differential patterning of smooth muscle cells (SMCs) and pericytes within specific blood vessels ultimately defines and distinguishes the functional properties of the arteries, veins and capillaries.
SMC phenotype and patterning, in turn, are determined via transcriptional programs that respond to developmental and environmental signals and cues.
We have used transgenic and gene targeting strategies to elucidate the transcriptional programs that regulate vascular SMC differentiation.
Our group and others have reported recently that the SAP domain transcription factor, myocardin, plays a critical role in SMC differentiation.
Preliminary studies presented herein demonstrate that: i) myocardin is expressed in a precise developmentally regulated pattern in vascular and visceral SMCs,
ii) forced expression of myocardin in non-SMCs activates multiple SMC-specific transcriptional regulatory elements,
iii) forced expression of myocardin activates SMC-restricted genes in undifferentiated embryonic stem (ES) cells, and
iv) expression of adominant-negative myocardin mutant protein or myocardin siRNA in SMCs represses activity of the SMC-specific SM22alpha-promoter. |
Function of GATA-6 in Vascular Smooth Muscle
Sponsor: NIH, Grant # K08HL075520, PI: John J. Lepore »
A 5-year training program to develop an investigative career in vascular biology. The program is designed for the applicant to obtain additional training in molecular and cellular biology
to complement his prior training in translational research and in the physiologic analysis of the cardiovascular system of mice. The field of research will be the transcriptional regulation of vascular smooth muscle cell (VSMC)
differentiation and phenotypic modulation, an area of significant importance to cardiovascular science and clinical cardiology.
Dr. Michael Parmacek, an internationally recognized expert in this field, will mentor the applicant's scientific development.
The research plan will focus on the function of the transcription factor GATA-6 in VSMCs. Other GATA transcription factors play critical roles in regulating cell-type differentiation and proliferation.
Dr. Parmacek's lab has previously demonstrated that GATA-6 is required for normal formation of the visceral endoderm during embryonic development; however, its precise function in VSMCs has not been determined. |
Arrhythmia Mechanisms of the Metabolic Sensor AMP Kinase
Sponsor: NIH, Grant # K08HL074108, PI: Vickas Patel »
A 5-year training program to develop an academic career in molecular cardiac electrophysiology. The principal investigator has extensive training in clinical cardiac electrophysiology, basic electrophysiology, biophysics,
and electrical engineering and will expand his scientific skills through a unique integration of interdisciplinary resources. This program will promote the command of molecular developmental biology,
as applied to the development of cardiac arrhythmias and conduction disorders. Dr. Michael Parmacek will mentor the principal investigator's scientific development.
He is a recognized leader in the field of molecular cardiac development and has trained numerous postdoctoral fellows and graduate students.
To enhance the training, an advisory committee of highly regarded medical scientists will provide scientific and career guidance. The research will focus on mechanisms of
arrhythmogenesis produced by mutations in the metabolic sensor AMP-activated protein kinase. |
Genetics of Elevated High Density Lipoprotein Cholesterol
Sponsor: NIH, Grant # R01HL089309, PI: Daniel J. Rader »
The syndrome of "familial hyperalphalipoproteinemia," or elevated high density lipoprotein cholesterol (HDL-C), is known to be associated with
longevity and protection from atherosclerotic cardiovascular disease. The only proven molecular etiology of familial hyperalphalipoproteinemia is
homozygous cholesteryl ester transfer protein (CETP) deficiency, which is found almost exclusively in Japan and led to the concept of pharmacologic
CETP inhibition as a strategy to raise HDL-C levels. We have recruited what we believe to be the largest existing cohort of non-Japanese probands with high
HDL-C cholesterol levels and their nuclear and extended families in order to determine novel genetic factors that cause elevated HDL-C.
We will perform a high density genome-wide SNP scan using the Illumina 550K chip and utilize these data for family-based tests of association to search for HDL-C QTL. |
Gene Therapy for Dyslipidemia and Atherosclerosis
Sponsor: NIH, Grant # P01HL059407, PI: Daniel J. Rader »
Dyslipidemia is a major risk factor for premature atherosclerotic cardiovascular disease (ASCVD). Although many patients with dyslipidemia can be treated effectively with existing drugs,
others are not effectively treated and remain at exceptionally high risk of premature ASCVD; the classic example is homozygous familial hypercholesterolemia (FH). Therefore, understanding of
the regulation of the secretion and catabolism of apoB-containing lipoproteins by the liver and the complex pathways of HDL metabolism is of major importance to the development of
new therapies targeted toward these pathways. Liver-directed somatic gene transfer is a useful biological tool for addressing hypotheses regarding the physiological effects of expressing specific
genes in the liver on apoB lipoprotein and HDL metabolism; furthermore, it could be a strategy for treating severe dyslipidemia.
In this project, we will utilize liver-directed gene transfer using vectors based on novel adeno-associated virus (AAV) pseudotypes to address questions related to the impact
of specific gene products and their interactions on the regulation of hepatic secretion of apoB-containing lipoproteins. |
Predictors of Anticoagulation Control on Warfarin
Sponsor: NIH, Grant # R01HL066176, PI: Stephen Kimmel »
Thromboembolism (TE) can occur in the venous or arterial system and is associated with substantial morbidity and mortality in a large proportion of the population.
Although most of these thromboembolic events can be prevented using warfarin sodium, proper levels of anticoagulation (AC) with warfarin are very difficult to maintain.
Because the drug has a narrow therapeutic range, inadequate levels of AC can lead to failure of therapy and life threatening thromboembolic complications, while excessive levels
can lead to life threatening bleeding complications. In addition, improper AC can lead to increased medical costs, reduced quality of life, patient dissatisfaction, and discontinuation
of a highly efficacious therapy. However, the reason for the marked intrapatient and interpatient variability in response to warfarin often remains unknown.
Recently discovered genetic variants that affect warfarin pharmacokinetics (the CYP2C9 enzyme, via reduced warfarin metabolism) may explain at least some of this variability. |
Genetics of Atherosclerosis in Renal Disease
Sponsor: NIH, Grant # R01DK071224, PI: Muredach P. Reilly »
Atherosclerotic cardiovascular disease (CVD) is an inflammatory disorder with a complex genetic basis.
Chronic kidney disease (CKD), a major risk factor for CVD, is rapidly increasing in the U.S. The mechanistic link between these diseases remains largely undetermined.
Recent studies suggest that insulin resistance, kidney dysfunction and CVD share common genetic bases. Innate immunity and insulin resistance converge in atherosclerosis
and are prominent features of CKD. We hypothesize that, in this setting, genetic variation in innate immune and insulin resistance pathway genes will contribute individually
and through multi-locus effects, to clinically important risk of CVD in the CKD population beyond traditional risk factors.
The Chronic Renal Insufficiency Cohort (CRIC) Study,
a prospective NIH sponsored multi-center study (n=3,000) of renal and CVD complications of CKD, provides a unique opportunity to examine these hypotheses. |
Mechanisms of Improved Diastolic Function in Human Heart
Sponsor: NIH, Grant # R01AG017022, PI: Kenneth Margulies »
As an endpoint for many different types of cardiovascular disease, heart failure (HF) is a leading cause of mortality and morbidity in the U.S.
Though some patients with HF have intact systolic function, virtually all patients with HF have abnormal diastolic function and an impaired ability to increase cardiac performance in response
to physiologic stress, including exercise. During exercise, myocardial responses to increased heart rate and adrenergic stimulation normally involve augmentation of cardiac filling
(requiring relaxation reserve) and enhanced ejection (requiring contractility reserve). At the cellular level, relaxation reserve, the focus of this application, requires faster decay of the
intracellular calcium (Ca) transient and a decrease in myofilament Ca sensitivity. Ordinarily, both processes are enhanced by beta- adrenergic stimulation triggering PKA-mediated
phosphorylation of key Ca regulatory and myofilament proteins. However, both relaxation reserved and adrenergic modulation of relaxation reserve are abnormal in failing hearts.
Recognizing that Ca cycling dynamics are themselves abnormal in failing myocardium, the broad objective of the proposed studies is to examine beta-adrenergic/PKA-mediated
modulation of relaxation reserve in failing human hearts in a manner that accounts for the defects in Ca cycling present in these hearts. |
Translational Studies in Heart Failure Gene Therapy
Sponsor: NIH, Grant # R01HL083078, PI: Charles R. Bridges »
This year, one million Americans will die of heart failure at a cost of 25 billion dollars.
Yet, only two thousand Americans will receive heart transplants and even fewer will receive mechanical ventricular assist devices.
Gene therapy is an important emerging technology with the potential to save thousands of lives.
Correction of the heart failure phenotype has been convincingly demonstrated in transgenic mice, rabbit and rodent models of heart failure using
the beta adreno-receptor kinase C-terminus (BARKct)) as a therapeutic transgene. Prior to our work, none of the delivery techniques utilized to date
has been clinically translatable and had high global myocyte transduction efficiency. These observations galvanize our central hypothesis:
the rate-limiter in the quest for clinically relevant heart failure gene therapy is the successful achievement of global vector-mediated
gene delivery to a significant percentage of cardiac myocytes in situ in a translational animal model. |
Angiogenic Tissue Engineering to Limit Post-infarction Ventricular Remodeling
Sponsor: NIH, Grant # R01HL089315, PI: Y. Joseph Woo »
Myocardial ischemia and infarction with resultant adverse ventricular remodeling and heart failure form an increasingly prevalent global health problem for which medical and surgical treatments are limited.
Innovative therapies are greatly needed. This proposal seeks to investigate and develop a novel acute endogenous revascularization therapy which upregulates endothelial progenitor cells (EPCs) and specifically
targets them to ischemic myocardium. This post- infarction angiogenic therapy to augment myocardial microcirculation will study three specific aims: 1) Mobilization and targeted chemokinesis of EPCs to
revascularize ischemic myocardium. 2) Angiogenic reengineering of regional myocardial biomechanical properties to attenuate adverse ventricular remodeling and improve cardiac function.
3) Translational preclinical large animal model testing of endogenous revascularization therapy utilizing progressively less invasive, clinically-available technologies. |
Cardiac Surgery Techniques to Treat Ventricular and Aortic Remodeling
Sponsor: NIH, Grant # U01HL088957, PI: Michael A. Acker »
We propose to study strategies for ameliorating adverse cardiovascular remodeling within the context of the Network for Cardiothoracic Surgical Interventions.
This proposal consists of two separate prospective randomized studies:
1) "Prospective Randomized Evaluation of Mitral Valve Repair for Functional Mitral Insufficiency and Ventricular Dysfunction" (Dr. Joseph Woo, Co-investigator)
2) "Adjunct Delivery of Aortic Stent Graft in the Descending Thoracic Aorta in Acute Type A Dissection Repair Obliterates the Residual False Lumen and
Prevents Aneurysmal Remodeling of the Distal Thoracoabdominal Aorta" (Dr. Joseph Bavaria, Co-investigator)
Each of the proposed studies addresses an important manifestation of adverse cardiovascular remodeling which currently
confront cardiologists and cardiac surgeons on a routine basis. Both studies will be done in a multi-disciplinary fashion with full collaborative
support from the Divisions of Cardiovascular Surgery, Cardiology, Vascular Surgery and Cardiac Anesthesiology. |
Strain Induced Myopathy in Post Infarction Heart Failure
Sponsor: NIH, Grant # R01HL076560, PI: Joseph H. Gorman »
Five million Americans suffer from congestive heart failure (CHF). Despite 30 years of advances in revascularization techniques coronary disease still accounts for 70% of all cases of CHF.
Once the diagnosis is made the 5-year mortality is 50%, regardless of treatment. We hypothesize that following acute myocardial infarction, infarct expansion occurs, which stretches adjacent perfused myocardium.
This stretching induces reactive oxygen species (ROS) mediated myocyte apoptosis, which results in progressive non-ischemic myopathic process that recruits additional contiguous, fully perfused, remodeled myocardium to cause dilated cardiomyopathy, CHF and death.
This project uses sonomicrometry array localization (SAL) to study a sheep model of post infarction left ventricular (LV) remodeling. |
Cardiac Gene Therapy
Sponsor: NIH, Grant # P01HL059407, PI: Lee Sweeney »
The proposed research seeks to delineate the mechanisms underlying the progressive development of dilated cardiomyopathy and failure following myocardial infarction.
We also will examine resetting of the calcium set point for contractility as a potential strategy to blunt hypertrophic drive resulting from pressure overload.
In doing so, we will evaluate AAV-gene transfer approaches for the treatment of heart failure. First we will evaluate the hypothesis that an apoptotic component drives the dilated cardiomyopathy that follows focal infarction. Lastly, we will alter the calcium sensitivity of the cardiac troponin complex in an attempt to blunt pressure overload hypertrophy and the subsequent progression to failure. |
Myosin Isozymes
Sponsor: NIH, Grant # R01AR035661, PI: Lee Sweeney »
The major questions remaining to be answered as to how myosin functions as a molecular motor surround the actin-activated product release steps.
We propose that we now have high-resolution structures that show us the starting (transition state) and ending (myosin V closed cleft or rigor-like state) structures of myosin
as it goes through its force-producing cycle. What we are lacking is any insight as to how the interaction with actin leads to the sequential release of phosphate and MgADP
that is coupled to movement. There are two major goals of this study. Our goal is to characterize key structural elements of myosin that are involved in the product release mechanisms.
We will make use of the fact that myosin V, non-muscle myosin MB, smooth muscle myosin II and Dictyostelium myosin II have kinetics that are fundamentally different from each other. |
Modulation of Muscle Growth for the Muscular Dystrophies
Sponsor: NIH, Grant # U54AR052646, PI: Lee Sweeney »
The muscular dystrophies are characterized by progressive loss of strength over time. Stimulating muscle growth may delay the time before significant disability and death.
The overall theme of this center is to study mechanisms to modulate muscle growth and breakdown for treatment of a variety of muscular dystrophies.
IGF-1 is a potent stimulator and myostatin a specific inhibitor of muscle growth. Modulation of both pathways has been shown to ameliorate the mdx model of muscular dystrophy.
Recently, protease inhibition with Bowman Birk Inhibitor Concentrate (BBIC) has been found to have similar effects. The center is composed of three sites,
Johns Hopkins, University of Pennsylvania and intramural NINDS and includes investigators who are leaders in the field of myostatin and IGF-1 as well as clinical experts in muscular dystrophy. |
Ectopic F.VIII Expression in Megakaryocytes: Treatment of Hemophilia A
Sponsor: NIH, Grant # P01HL064190, PI: Mortimer Poncz »
Platelets adhere, form a platelet plug and degranulate at sites of vascular injury. We are interested in testing whether ectopically expressed proteins during megakaryopoiesis would be stored within
platelets and released at sites of injury, modulating the thrombotic process. Initial transgenic studies suggest that we can accomplish this process, delivering platelet-released (p) Factor VIII (FVIII)
to a site of injury to improve the bleeding diathesis in FVIIInull mice. We propose to better understand and improve on the transgenic pFVIII model, and to extend these studies to a gene therapy approach.
We believe that successful application of these ideas may provide new approaches for the management of Hemophilia A and perhaps other diseases affecting thrombus formation. |
Mechanisms of Cardiopulmonary Gene Transfer
Sponsor: NIH, Grant # R01HL066565, PI: Scott L. Diamond »
Achieving the full potential of intraarterial, intravenous, or pulmonary gene therapy requires quantitative bioengineering analysis of extracellular and intracellular barriers.
The central focus of this proposal is to achieve high expression of transgenes delivered to cardiovascular and cardiopulmonary cells such as arterial endothelium and airway epithelium.
We will bioengineer and investigate sterol, peptide, and polymer- based transfection vehicles for their ability to enhance gene transfer. |
Targeting Carriers with Controlled Geometry to Endothelium
Sponsor: NIH, Grant # R01HL087036, PI: Vladimir Muzykantov »
Drug targeting to endothelial cells (EC) will help to attain more specific and effective treatment of a plethora of maladies including inflammation. We found that targeting prototype nanocarriers and cargoes
to the endothelial Cell Adhesion Molecules (CAMs) ICAM-1 and VCAM-1, differentially expressed by resting vs pathologically altered EC, provides prophylactic and therapeutic drug delivery into EC.
Further, ICAM-targeted nanoparticles transfer across EC without damage to the cells. Flow conditions, affinity and geometry of anti-CAM carriers govern their biological behavior, EC targeting and sub-cellular destination.
Targeted delivery of drugs to endothelial cells lining vasculature will advance treatment of many health maladies. In this grant, we will design and test a novel drug delivery platform based on
targeted recognition of endothelial surface determinants by polymer nanocarriers loaded by anti-inflammatory and other therapeutic agents. |
Blood Systems Biology
Sponsor: NIH, Grant # R33HL087385, PI: Lawrence Brass »
The University of Pennsylvania, in response to RFA-HL-06-004, has assembled an interdisciplinary team of faculty from the School of Engineering and Applied Sciences and the School of Medicine
with expertise in experimental and computational hemodynamics, bond mechanics and biorheology, transport physics, platelet biology, coagulation and protease biochemistry, continuum/stochastic simulation,
inverse problems, and knockout mice for thrombosis research. The Cluster Team will deploy integrative and hierarchical computational models and experimental studies to predict spatial-temporal processes
in mouse and human blood under hemodynamic conditions.Better elucidation and quantitative simulation of blood reactions and platelet signaling pathways under hemodynamic conditions are directed at
clinical needs in thrombosis risk assessment, anti-coagulation therapy, platelet targeted therapies, and stroke research. |
Inflammatory Response to Sleep Apnea in Obese Subjects
Sponsor: NIH, Grant # R01HL080076, PI: Frederick Samaha »
Obstructive sleep apnea (OSA) is associated with an increased risk for cardiovascular events. Whether the mechanism for this association is
directly attributable to pro-atherosclerotic effects of OSA or primarily related to obesity is not known. Obesity is common in patients with OSA,
and is itself associated with an inflammatory state and insulin resistance. In individuals with both obesity and OSA, the repetitive hypoxia associated
with OSA may promote inflammation and insulin resistance. Our primary aim is to test the hypothesis that OSA plays a primary role in the
inflammatory state of patients with obesity and moderate-severe OSA, and that therefore the elimination of apnea by continuous positive airway pressure
(CPAP) therapy in these patients will more greatly reduce inflammation (measured by C-reactive protein or CRP) than weight loss alone, and that
combining these two therapies will have additive effects on reducing inflammation. |
Aging, Insulin Resistance, and Dilated Cardiomyopathy
Sponsor: NIH, Grant # R01AG023125, PI: Richard P. Shannon »
Congestive heart failure is a leading cause of morbidity and mortality in the elderly, although the mechanisms to explain the enhanced proclivity are poorly understood.
It remains debatable as to whether the age-associated propensity to cardiovascular dysfunction is attributable to aging per se or the accumulation of
cardiovascular risk factors that accrue over time. In particular, aging has been closely associated with the development of increased visceral adiposity
that has been implicated in the pathogenesis of age associated insulin resistance. Whether age associated insulin resistance contributes to the progression of
cardiac dysfunction following myocardial injury has not been explored systematically. |
Chronic Cocaine Effects on Normal and Diseased Hearts
Sponsor: NIH, Grant # R01DA010480, PI: Richard P. Shannon »
Chronic cocaine abuse remains a considerable public health problem among the nation's adolescent and young adult populations.
In addition to the recognized psychosocial burdens associated with cocaine abuse, there are serious physiological consequences that remain poorly understood.
Most prominent among the pathophysiological consequences are the cardiovascular toxicities attributed to chronic cocaine use.
Myocardial ischemia and infarction and cardiomyopathy remain the most serious cardiovascular consequences of cocaine use in humans
and a prominent cause of premature morbidity and mortality among the nation's youth. |
Home Heart Failure Care Comparing Patient-Driven Technology Models
Sponsor: NIH, Grant # R01HS015459, PI: Lee R. Goldberg »
This is a study is to assess the impact of health information technologies (HIT) on clinical and financial outcomes for patients with symptomatic heart failure (HF).
Nearly 5 million Americans have HF (the leading cause of hospitalization) with an estimated $40 billion annual cost. The information technologies we will use include remote monitoring (telemonitoring)
of vital signs and symptoms, an electronic health record system and clinical decision support systems. We will test a reproducible model for technology-supported HF management and assist purchasers,
payers and policy makers in selecting HIT to improve clinical and financial outcomes. Patients will be recruited from rural and urban primary care practices. We will evaluate two different configurations of HIT.
Recent publication: Caveat emptor: the need for evidence, regulation, and certification of home telehealth systems for the management of chronic conditions |
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