GATA4 as a Modulator of Aortic Root Sensitivity to Mechanochemical Disruptions Caused by an Aneurysm-causing Mutation

点击翻译按钮获取中文摘要

PROJECT SUMMARY Aortic aneurysms are localized dilations that predispose the vessel to dissection or rupture, both of which are associated with high mortality. Loeys-Dietz Syndrome (LDS) is a hereditary aneurysm disorder caused by mutations that impair, but do not fully disrupt, TGF-β signaling. LDS patients have a strong predisposition for disease in the aortic root even though the genes that are mutated in this condition are ubiquitously expressed throughout the vasculature. The mechanisms that underlie this localized vulnerability remain unclear. In this proposal, I will test the hypothesis that intrinsic factors expressed in smooth muscle cells present in the aortic root render them more susceptible to the mechanochemical disruptions of the aorta caused by LDS mutations. Specifically, I will investigate if intrinsic expression of Gata4 in a subset of vascular smooth muscle cells primes these cells to upregulate GATA4 when homeostatic inhibitory mechanisms that depend on proper contacts between these cells and the extracellular matrix fail. I will be supported by my sponsor, Dr. MacFarlane, and co-sponsor, Dr. Dietz, to complete the following aims. In Aim 1, I will uncover how LDS mutations affect aortic extracellular matrix structure and signaling downstream of focal adhesions and examine the effect of pharmacological interference with these pathways on aneurysm pathogenesis. In Aim 2, I will clarify the role of GATA4 in the pathogenesis of aortic root aneurysm by examining the effect of postnatal smooth muscle specific deletion of Gata4 on aortic root dilation. With the help of my collaborator, Dr. Kagohara, who is an expert in spatial transcriptomics, I will also learn use this cutting-edge technology and related computational tools to map the gradient of transcriptional heterogeneity along the length of the aorta. I will further develop my skills as an independent researcher and enhance my expertise in cardiovascular biology by completing focused coursework and regularly attending and presenting at scientific conferences. To improve my skills in scientific communication, I will seek out additional mentoring and teaching opportunities, including teaching an undergraduate genetics course at Johns Hopkins University. By completing this proposal, I will acquire the experience and skills necessary to attain a position as a postdoctoral fellow, and ultimately establish an independent academic career in cardiovascular research.