Thursday, April 3, 2025
4/3/2025
Cilia and Valvular Heart Disease - PROJECT SUMMARY Based on genetic and cellular discoveries made in the PI lab and his collaborators, this proposal focuses on novel mechanisms that are critical for formation of heart valves. Data presented in the proposal are an evolution of our studies presented in the first round of funding and show that mutations in the DZIP1 gene cause a very common heart valve disease (i.e., mitral valve prolapse) and can be caused by errors in how valve tissue forms during development. These discoveries have led to a novel concept that cilia are involved in valve development. While the function of DZIP1 is a focus of our studies in this proposal, we will also define new mechanisms by which the cardiac valves establish a trilaminar ECM organization and how this can feed back to the cells to suppress ciliogenesis in specific regions of the valve. Our studies will provide unique opportunities to answer questions about heart-valve diseases that heretofore have been impossible to answer using even state-of-the- art biological and genetic approaches. Valvular heart disease is a serious clinical problem, affecting 5-7% of the human population. Its complications include congestive heart failure, endocarditis, atrial arrhythmias, and sudden death. There are no known non- surgical cures for this group of disease. The proposed work capitalizes on previously unrecognized genetic data collected from heart valve disease patients; studies in the mouse show that this class of genes is an important and previously unrecognized contributor to valve structural development and disease pathogenesis. The uncovering of this particular disease gene and the processes it regulates holds great potential for future remedial or therapeutic insight towards regeneration or formation of mechanically stable valve tissue that will be beneficial to valvular heart disease patients.
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