Friday, May 9, 2025
5/9/2025
Gene Regulatory Mechanisms of the Coronary Artery Disease Gene PRDM16 on Smooth Muscle Cell Phenotypic Modulation - PROJECT SUMMARY/ABSTRACT Despite decades of progress, coronary artery disease (CAD) remains the top global cause of death. While hundreds of CAD-associated genes have been identified, the translation into new treatments has been hampered by a lack of understanding of the molecular mechanisms tying these genes to disease risk. Although smooth muscle cells (SMCs) harbor much of the attributable risk for CAD and comprise the main cellular component of diseased vessels, no currently available treatments target these cells directly. As CAD progresses, SMCs undergo a complex process of phenotypic modulation, where SMCs migrate, proliferate, de- differentiate, and transition into other cellular states, including protective “fibromyocytes” (FMC). The candidate, Dr. Brian Palmisano, has developed strong preliminary data that support the CAD- associated gene, PR domain containing 16 (PRDM16), is a critical regulator of SMC phenotypic modulation. PRDM16 is an epigenetic modifier involved in cell state transitions in several cell types, and is highly expressed in vascular tissues, but its role in SMC phenotypic modulation and atherosclerosis is currently unknown. The candidate’s preliminary data indicate that SMC-specific loss of Prdm16 in an animal model of atherosclerosis leads to an increase in FMC development. In human coronary SMCs, overexpression of PRDM16 regulates SMC phenotypic modulation. As an epigenetic modifier with histone methyltransferase activity, PRDM16 also altered the enrichment of several histone methylation marks at genes related to SMC phenotypic modulation. This led to the candidate’s central hypothesis that PRDM16 regulates SMC phenotypic modulation and the transition to FMCs through its epigenetic modification of chromatin substrates, which will be tested in three specific aims. Aim 1 will determine the regulatory mechanisms by which PRDM16 suppresses SMC phenotypic modulation in vitro. Aim 2 will determine the gene regulatory networks underlying Prdm16-mediated phenotypic modulation of SMCs in vivo. Aim 3 will determine the downstream factors governing PRDM16-mediated phenotypic modulation of SMCs in vitro. The enclosed training plan encompasses research, mentoring and career development activities that have been specifically formulated to develop the scientific and professional skills necessary for Dr. Palmisano to transition to an independent physician scientist studying novel molecular mechanisms of atherosclerosis. Dr. Palmisano will develop his skills in bioinformatic integration of multi-omic datasets and smooth muscle cell function under the mentorship of his primary mentor, Dr. Tom Quertermous, co-mentor, Dr. Josh Knowles and his expert advisory committee, each with expertise in multi-omic data analysis and mentorship of physician scientists. Collectively, these studies will identify the molecular mechanisms by which the CAD-associated gene PRDM16 regulates SMC phenotypic modulation, a critical process related to CAD disease risk, allowing Dr. Palmisano to launch his independent career as a physician scientist.
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