Date of Award

2020

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Regenerative Medicine and Cell Biology

College

College of Graduate Studies

First Advisor

Russell Norris

Second Advisor

Joshua Lipschutz

Third Advisor

Stephen Duncan

Fourth Advisor

Andy Wessels

Fifth Advisor

Lauren Ball

Abstract

Mitral valve prolapse (MVP) and bicuspid aortic valve (BAV) are serious heart conditions that affect a combined 3-4% of the world population. These diseases carry high risk for secondary complications including arrhythmia, blood regurgitation, and sudden cardiac death. Often, valve diseases are heritable and have complex origins that are not fully understood. The lack of knowledge about valve disease causation likely contributes to the absence of non-surgical treatment options for this patient population. Recent work by our lab and others has demonstrated a link between defects in primary cilia and the development of heart valve disease in humans. Primary cilia are singular, non-motile, microtubule-derived, signaling organelles that are ubiquitous to most cell types. In cardiac valves, they are spatially and temporally regulated, appearing primarily on interstitial cells during valvulogenesis. This dissertation presents evidence that ciliogenesis in the valves is dependent on a highly conserved octameric protein trafficking complex known as the exocyst. We demonstrate that defects in exocyst trafficking result in shorter, less prevalent cilia, the development of bicuspid aortic valves and myxomatous mitral valves in mice, and arterial stenosis in zebrafish. We also uncovered links between ciliome variants and BAV in humans through GWAS analysis. Additionally, we present findings that establish Desert Hedgehog (DHH) signaling as a necessary ciliary signaling pathway in valvulogenesis. Through morphometric analysis of murine mitral valves and biochemical in vitro studies with embryonic chicken valve cells, we describe a novel paracrine crosstalk mechanism emanating from the DHH expressing endocardium that influences the production of alpha smooth muscle actin (a-SMA) by the ciliated valve interstitial cells to promote valve remodeling. This newly generated hypothesis will guide future studies and may provide mechanistic insights of ciliopathies in other tissues. This project led to a new understanding of valve development and highlights the importance of the exocyst, primary cilia, and Desert Hedgehog signaling in valve morphogenesis. Genetic defects in any portion of this system result in faulty valve architecture and disease progression. Insights from this work will inform future discoveries into disease origins and progression and potentially lead to the identification of therapeutic targets for cardiac valve diseases.

Rights

All rights reserved. Copyright is held by the author.

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