Regulation of atrioventricular canal restriction by Tmem2

Doctor's Name: 
Dr. Lucile Ryckebusch
University of California, San Diego

Collaboratively awarded through the CHF and AHA Congenital Heart Defect Research Awards
(Total Grant Amount $51,840; CHF portion = $25,920)

The cardiac atrioventricular (AV) valve is a highly specialized anatomical structure that prevents regurgitation of blood flow between the cardiac chambers. As such, correct valve development is required for appropriate hemodynamics of circulation. The AV valve develops in a discrete region of the heart, the AV canal (AVC). The long-term goal of my research is to understand the molecular mechanisms that regulate the specification and differentiation of the AVC and make it distinct from the adjacent cardiac chambers. Currently, my work focuses on the role of the transmembrane protein Tmem2, an important player in restricting the boundaries of the AVC. With support from an AHA postdoctoral fellowship, I have shown that Tmem2 confines AVC differentiation by limiting Wnt signaling. Here, I propose to build upon this work by delving deeper into the mechanism through which Tmem2 influences Wnt signaling and by establishing which domains of Tmem2 are required for its function. In this one-year proposal, I aim to (1) test whether Tmem2 restricts Wnt signaling by modulating the extracellular matrix, and (2) determine which domains of Tmem2 are required for restriction of AVC differentiation. Together, these studies will provide new insights regarding poorly understood mechanisms underlying AV valve development and will help us to understand how these processes could be disrupted by congenital heart disease.

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