CAREER: Vascularization in Cardiac Fibrosis Models

California State University-Long Beach Foundation, Long Beach CA

Investigators

Abstract

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). Heart failure (HF) persists as a major healthcare issue because of its high prevalence, mortality, morbidity, and cost of care. The human heart has limited capacity of repair after injury, and the lost cells are replaced by a fibrotic scar. The limited formation of blood vessels during cardiac fibrosis conditions significantly contributes to disease progression; vascularization in a damaged heart muscle is still a central and unresolved problem for cardiac muscle infarction repair. The objective of this CAREER proposal is to use a tissue engineering approach to develop precise diseased models to investigate vascular repair of damaged cardiac fibrotic tissue, and to integrate inclusive education and research training to every stage of the research work. This system will enable investigation of effective therapies for patients suffering with heart disease and the training component will broaden the participation of women and students from underrepresented backgrounds in science and engineering, eventually helping to diversify America's science and engineering workforce. The investigator's long-term research goal is to advance strategies to engineer novel tissue models that mimic matrix remodeling and vascularization events during different pathophysiological conditions e.g., fibrosis progression after myocardial infarction, aiming to gain insight on tissue repair mechanisms and to ultimately establish new therapeutic approaches to control cardiac dysfunction and repair. Towards this goal, the aim of this CAREER project is to increase understanding of the mechanisms of vascularization in cardiac fibrosis conditions. The proposed 3D models will mimic important characteristics of the infarcted fibrotic cardiac tissue. The research objectives are to: (1) Engineer well-defined cardiac fibrosis models that recapitulate the remodeling process post-MI, (2) Determine/replicate the reciprocal influence of endothelial cells on the progression of cardiac fibrosis and the role of fibrosis on vascularization, and (3) Investigate the design of a vascularized engineered cardiac fibrosis model with flow that could help elucidate mechanisms to enhance cardiac vascularization and repair. The results obtained from this study will focus on two important aspects that limit the success of regenerative therapies for cardiac regeneration, the progression of fibrotic tissue remodeling and the optimal approach to promote sustained cardiac vascularization. This knowledge will contribute to the development of novel approaches to modulate the balance between pathological fibrosis and endogenous mechanisms of regeneration, including angiogenesis. New insight will facilitate the development of advanced regenerative therapies that can be implemented in the clinic. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.