Penn Cardiovascular Institute

Margulies Lab

Contact the Lab

Kenneth B. Margulies, MD

Kenneth B. Margulies, MD
Principal Investigator

Tramel Parker, Administrative Assistant
11-101 Smilow Center for Translational Research
Perelman School of Medicine
3400 Civic Center Blvd., Bldg. 421
Philadelphia, PA
Office: 215-573-4717
Tramel.Parker@uphs.upenn.edu

Kenneth Margulies, MD
11-101 Smilow Translational Research Center
3400 Civic Center Boulevard, Bldg. 421
Philadelphia, PA 19104-5156
215-573-2980
ken.margulies@uphs.upenn.edu

Overview

The Margulies Lab examines mechanisms of myocardial remodeling to identify targets for therapeutic interventions. Many of the inquiries are initiated by multilevel examinations of explanted human heart tissues obtained at the time of transplantation or organ donation to permit insights into both the heterogeneity of myocardial adaptations to disease and identification of dominant mechanisms and responses.

In addition to a longstanding focus on load-dependent myocardial remodeling and adaptations to LVAD support, the lab is actively engaged in studies of endogenous myocardial repair, integrative genetic and genomic inquiries designed to identify molecular mechanisms modifying disease susceptibility, myocardial tissue engineering and patient-based proof-of-concept studies.

Research Projects

Integrative Genomics of Human Heart

The Margulies and Cappola Labs lead a consortium of large heart transplant centers, including Penn, Stanford and the Cleveland Clinic to identify genetic variants that influence myocardial gene expression in normal and failing human hearts. Complementary studies relate the results of the expression quantitative trait loci (eQTL) analysis to recent genome-wide association (GWAS) studies and explore the functional biology of newly implicated genes and pathways. These investigations are identifying new molecular targets for mechanistic and therapeutic studies and are establishing a durable web-based DataResource and associated BioResource to allow access by the scientific community to data and specimens.

Engineered Cardiac Microtissues (CMTs)

Together with Chris Chen's Lab, the Margulies Lab is developing and optimizing mechanically loaded, functional, 3-dimensional (3D) CMTs comprised of cardiac myocytes and supporting cells to facilitate mechanistic studies and preclinical drug screening. Microfabication techniques generate arrays of 3D CMTs embedded within silicon (PDMS) matrices and microcantilevers in the matrices simultaneously constrain CMT contraction and report forces generated by the CMTs in real time. The labs have generated CMTs using both neonatal rodent myocytes and human iPS-derived myocytes. Ongoing studies are examining the effects of alterations in biomechanical load, electrical stimulation, varying cellular constituents, growth factors and extracellular matrix dynamics on the function and morphology of CMTs. Complementary morphological assessments and cell-type specific gene expression, secreted proteins and fluorescent reporters will be used to assess CMT maturity and the phenotypes of myocytes and fibroblasts within CMTs.

Studies of Endogenous Cardiac Repair

Recognizing that defects in myocardial energy metabolism are present in virtually all types of heart failure, recent collaborations have examined myocardial energy stores and mitochondrial DNA damage. We have also been examining the effects of GLP-1 in mouse models of ischemia-reperfusion injury and human myocardial tissues. Within the NIH-sponsored Heart Failure Clinical Research Network, we are leading a phase II clinical trial of GLP-1 Agonist Therapy in patients with advanced heart failure due to systolic dysfunction.

Selected Publications

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