Research Description

Integrative Genomics of Human Heart. We are leading a consortium of three large US heart transplant centers (Penn, Stanford and Cleveland Clinic) and others that are employing existing biobanks and newly procured specimens to identify genetic variants that influence myocardial gene expression in > 1,800 normal and failing human hearts. Complementary studies will relate the results of the eQTL analysis to recent GWAS studies, define cell type-specific gene expression and examine expression profiles in human hearts with intermediate disease severity phenotypes. These studies are identifying new molecular targets for mechanistic and therapeutic studies and are establishing a durable web-based DataResource and associated BioResource consisting to allow access to the data and specimens by the scientific community. Ongoing studies include further characterizations of samples with RNA sequencing and integration with DNA and histone methylation and digital pathology characterizations.

Engineered Cardiac Microtissues (CMTs). In collaboration with faculty from Penn's School of Engineering and Applied Science, we are developing and optimizing mechanically loaded, functional, 3-dimensional (3D) CMTs comprised of cardiac myocytes and fibroblasts 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. We 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, 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. We are also adapting this model for high throughput monitoring of drug-induced changes in contractility and growth.

Studies of Myocardial Metabolism in Heart Failure. These studies include metabolomic profiling of human heart tissues from patient with and without heart failure and patients with and without diabetes mellitus. Studies are identifying novel shifts in cardiac substrate utilization that may alter regulatory pathyways relavent to metabolism and other processes. A separate line of inquiry with Dr. Florin Despa's laboratory at the University of Kentucky has been examining the role of islet-derived amylin polypeptides and oligomers as contributors to target organ (heart, kidney, brain) dysfunction in patients with type-2 diabetes mellitus. In clinical studies, 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.

Studies of Endogenous Cardiac Repair. We have been characterizing the immunophenotypes and capacity cardiac myocyte differentiation of resident stem cells in human hearts. We have also been studying mechanisms of stem cell engraftment to the injured heart with the goal of enhancing ordinarily poor engraftment rates observed in most clinical trials. We are collaborating on preclinical and clinical trials that are using local chemokine delivery to enhance endogenous stem cell engraftment to the heart.