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.
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. Microfabrication 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.
- Quaile MP, Rossman EI, Berretta RM, Bratinov G, Kubo H, Houser SR, Margulies KB. Reduced sarcoplasmic reticulum Ca(2+) load mediates impaired contractile reserve in right ventricular pressure overload. J Mol Cell Cardiol. 2007;43:552-563. [PMID: 17931654]
- Margulies KB, Matiwala S, Cornejo C, Olsen H, Craven WA, Bednarik D. Mixed messages: transcription patterns in failing and recovering human myocardium. Circ Res. 2005;18:592-599. [PMID: 15718504]
- Hannenhalli S, Putt ME, Gilmore JM, Wang J, Parmacek MS, Epstein JA, Morrisey EE, Margulies KB, Cappola TP. Transcriptional genomics associates FOX transcription factors with human heart failure. Circulation. 2006;114:1269-1276. [PMID: 16952980]
- Kubo J, Jaleel N, Kumarapeli A, Beretta R, Bratinov G, Shan X, Wang H, Houser SR, Margulies KB. Increased cardiac myocyte progenitors in failing human hearts. Circulation. 2008;118:649-657. [PMID: 18645055]
- Quaile MP, Kubo H, Kimbrough CL, Douglas SA, Margulies KB. Direct inotropic effects of exogenous and endogenous urotensin-II: divergent actions in failing and nonfailing human myocardium. Circ Heart Failure. 2009;2:39-46. [PMID: 19808314]
- Shan X, Quaile MP, Monk JK, French B, Cappola TP, Margulies KB. Differential expression of PDE5 in failing and non-failing human myocardium. Circ Heart Fail. 2012;5:79-86. [PMID: 22135403]
- Shan X, Margulies KB. Differential regulation of PDE5 Expression in left and right ventricles of feline hypertrophy models. PLoS One. 2011; 6:e19922. [PMID: 21625548]
- Elser JA, Purcell BP, Allana IA, Burdick JA, Margulies KB. Ischemia induces P-selectin-mediated selective progenitor cell engraftment in the isolated-perfused heart. J Mol Cell Cardiol. 2012;52:105-112. [PMID: 22047808]
- Boudou T, Legant WR, Mu A, Borochin MA, Thavandiran N, Radisic M, Zandstra PW, Epstein JA, Margulies KB, Chen CS. A microfabricated platform to measure and manipulate the mechanics of engineered cardiac microtissues. Tissue Eng Part A. 2012;18:910-919. [PMID: 22092279]