Date of Award

Summer 8-21-2015

Level of Access Assigned by Author

Campus-Only Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Viravuth P Yin

Second Committee Member

Leif Oxburgh

Third Committee Member

Sandra Rieger

Abstract

Despite current treatment therapy, heart failure remains the leading cause of mortality in the Western world, due to a very limited capacity for cardiac muscle regeneration. For instance, in response to myocardial infarction, the mammalian adult heart replaces the necrotic myocardium with rigid, permanent, collagen-laden scar tissue, resulting in deleterious changes in heart function. In contrast, the adult zebrafish heart responds to injury with complete regeneration of cardiac tissue by coupling de novo creation of cardiomyocytes (CMs) with scar tissue resolution to restore heart function. While the majority of current cardiac regeneration studies center on stem cells and induced pluripotent stem cells, there is increasing evidence, in the adult zebrafish and neonatal mouse that newly regenerated cardiac muscle emerges from an existing population of CMs. Therefore, a more directed effort to elucidate the genetic regulatory networks that encourage natural regeneration from injured tissue itself will be invaluable for improving human cardiac health. This thesis work advances our understanding of natural heart regeneration in two different ways: 1) The work documents the dual roles of the miR-101/fosab circuit in coordinating scar tissue removal, CM proliferation and new cardiac muscle synthesis. 2) Functional studies of miR-101 highlight the importance of the injury environment to control CM proliferative capacity. To the best of our knowledge, this is the first demonstration that dynamic expression of a single genetic factor pilots two fundamental cellular heart regeneration programs.

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