Investigating the role of electrical stimulation in integrin-mediated functionali

Columbia Univ New York Morningside, New York NY

Investigators

Abstract

DESCRIPTION (provided by applicant): High fidelity models engineered myocardium are expected to serve as an important tool in screening therapeutic drug targets in a surrogate 'in vivo' setting, and may additionally serve as replacement muscle in vivo after myocardial infarction. Guiding functional assembly or heart tissue in vitro depends on creating a 'biomimetic' environment, integrating the biochemical and physical cues present in the developing embryo. Understanding the complex interplay of these stimuli is instrumental in understand how tissues develop, and also to understand how tissue function fails in disease. Despite advances in engineering cardiac tissues, progress in developing functionally and morphologically advanced models of myocardium is still needed. The addition of physical stimuli, such as dynamically loaded and electrical stimulation has contributed to improved contractility and Ca+2 handling, yet the mechanisms through which this occurs remain unclear. We propose that electrical stimulation induced expression of integrins affects the functionality of engineered myocardium (EM). Integrins, which function as important bidirectional mechano-sensors, transmitting information between cells and their extracellular matrix, are especially important in the heart, guiding cell morphology, organization of the contractile apparatus, and mediating extracellular signals. I aim to investigate how integrin signaling affects the contractilty of Engineered Myocardium, and propose that they may act through two putative mechanisms: (1) guiding organization and Calcium handling in cardiomyocytes; (2) activating the release of soluble factors (TGF-¿1) from the extracellular matrix to induce downstream effects on cell function. The proposed studies will aim to contribute to our understanding of how electrical stimulation can be used to govern biological behaviors in engineered tissues, and further our understanding of the process of functional tissue assembly. Ultimately, a combination of biochemical and physical signals, as in development, will allow us to generate high fidelity in vitro models of healthy and diseased tissue as a testing platform for therapeutic interventions, as well as therapeutic patches of replacement muscle. Such testing platforms will alleviate the burden of cardiovascular disease, in reducing costs and minimizing risks in pre-clinical screenings of drugs, and eventually by alleviating the progression of heart failure, through replacement of contractile muscle in the damaged heart.