Saturday, May 18, 2024
5/18/2024
PROJECT ABSTRACT Coronary artery disease (CAD) is the worldwide leading cause of death, highlighting a critical need for additional therapies beyond what is currently available. Furthermore, the dramatic rise in obesity and type 2 diabetes (T2D) threatens to derail progress in treatment of CAD over the last 50 years. Obesity causes insulin resistance, which increases the risk of CAD both directly and indirectly, through the development of T2D and through the associated abnormalities of the metabolic syndrome – dyslipidemia, hypertension, high waist-hip ratio, and elevated glucose. There are few treatments available for insulin resistance and metabolic syndrome despite affecting nearly 30% of the US. Additionally, despite discovery of >200 genetic loci associated with CAD and >320 loci associated with insulin resistance related metabolic traits, the translation of these genetic insights into genetically driven therapies has been stagnated by the lack of understanding of the mechanistic connection between of CAD and insulin resistance. This proposal aims to determine the mechanistic connection of the gene PRDM16 (PR domain containing 16), which is associated with both CAD and insulin resistance related metabolic traits, to atherosclerosis. PRDM16 is known to regulate insulin resistance through regulation of brown and beige adipose tissue function. However, the role of PRDM16 in atherosclerosis is unknown. PRDM16 is a promising causal gene in CAD due to its high expression in vascular tissues and smooth muscle cells (SMCs); its high correlation with markers of SMC function; its interaction with other known CAD loci; and its interaction with important CAD signaling pathways. The applicant’s central hypothesis is that PRDM16 promotes CAD risk through epigenetic regulation of gene networks that modulate SMC phenotype to promote atherosclerosis risk. The applicant’s primary sponsor, Dr. Tom Quertermous, has developed a paradigm of SMC phenotypic modulation whereby SMCs de-differentiate, proliferate and migrate in response to atherogenic stimuli. This paradigm was developed using high resolution single cell sequencing technologies. Leveraging this platform, the application will test their hypothesis through two proposed aims. In Aim 1, the applicant will determine the impact of Prdm16 on vascular SMC function in atherosclerosis. In Aim 2, the applicant will determine the impact of Prdm16 on SMC phenotypic modulation using single cell sequencing technologies. The applicant will test these aims using a novel mouse model whereby Prdm16 is deleted from SMCs as well as by using molecular perturbations of PRDM16 in complementary in-vitro approaches. The proposed work will discover the causal role of PRDM16 in atherosclerosis and the fundamental role of PRDM16 in vascular SMC biology. Additionally, this work will identify a novel pathway connecting both CAD and insulin resistance, which will lay the foundation for discovery of novel therapies that may treat both CAD and insulin resistance.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
