Cell-autonomous control of heart progenitors in niche

Doctor's Name: 
Dr. Chulan Kwon
Hospital/Institution: 
Johns Hopkins

Collaboratively awarded through the CHF and AHA Congenital Heart Defect Research Awards
(
Total Grant Amount = $166,320; CHF portion = $83,160)

Congenital heart disease remains the most frequent type of birth defect and the leading cause of birth defect-related deaths in humans. Cardiac progenitor cells (CPCs)¿identified in early embryos or differentiating pluripotent stem cells serve as building blocks to make the heart during embryogenesis and abnormal CPC development is closely associated with the etiology of congenital heart disease. Thus, it is crucial to understand the biology of CPCs and their microenvironment. However, CPCs are highly heterogeneous and it is unknown if they undergo self-renewal. Consequently, understanding the precise mechanisms of CPC maintenance remains a fundamental challenge. We identified an undifferentiated and expansive population of CPCs and their niche during development, and this proposal aims to elucidate the mechanisms of CPC renewal regulated by the cell-autonomous factors Numb family proteins (NFPs Numb and Numb-like) and integrin b1 in the microenvironment. Specifically, we will determine (1) if NFPs play an instructive role for CPC renewal and expansion and (2) if NFPs regulate Integrin b1 degradation for CPC maintenance. With these aims, I expect to elucidate the cell-autonomous factors and mechanisms by which CPCs are maintained in a renewing and expansive state in their microenvironment. This knowledge will provide first insights into the mechanistic understanding of the self-renewal of CPCs in their niche during heart development, which will open up new avenues of research in congenital heart disease.

Award Date 1: 
2015
Award Amount 1: 
$83,160