Causal Mechanisms of Novel Gut-Hormone Agonists on Cardiovascular Health - PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) remains among the leading causes of death worldwide. Diabetes and obesity represent two modifiable risk factors for the development of CVD, but their prevalence is on the rise. Ongoing research efforts have successfully leveraged endogenous gut hormone signaling pathways for the treatment of diabetes and obesity. Long-acting Glucagon-like peptide-1 receptor (GLP-1R) agonists have demonstrated immense therapeutic potential for the treatment of diabetes and obesity by eliciting robust reductions in body weight and hemoglobin A1C. Moreover, GLP-1R agonists have also been shown to offer cardiovascular benefits and reduce cardiovascular events in patients with diabetes and obesity. In addition to single GLP-1R agonists, novel monomolecular dual (GLP-1R and glucose-dependent insulinotropic polypeptide receptor[GIPR]) and triple (GLP-1R, GIPR, and glucagon receptor [GCGR]) agonists have recently been developed and implemented. While the predominant mechanisms of action of single, dual, and triple agonists pertaining to insulin secretion, satiety, and gastric emptying are well understood, we lack a complete understanding of their effects on the cardiovascular system. The objective of this proposal is to investigate the cardiovascular impact of these novel agonists by comprehensively profiling the transcriptomic, epigenomic, and functional responses to semaglutide (GLP-1R), tirzepatide (GLP-1R/GIPR), and retatrutide (GLP- 1R/GIPR/GCGR) both in vitro and in vivo. Using human induced pluripotent stem cell (iPSC) technology, we will pool >20 individual iPSC lines from diverse donors to generate a “cell village” of iPSC-derived endothelial cells (iPSC-ECs) and cardiomyocytes (iPSC-CMs), enabling paralleled characterization via single-nuclear RNA and ATAC-sequencing (snRNA/ATAC-seq). Simultaneously, we will attain a cardiovascular functional profile of tirzepatide and retatrutide-treated healthy and diet-induced obese (DIO) mice using echocardiography, coronary flow reserve, and myography, while cardiac and aortic tissues will be subjected to snRNA/ATAC-seq. GLP1R variants will be introduced into iPSC using CRISPR/Cas9 and drug-responses will be profiled. The fellowship training plan was assembled to maximize my potential as a future investigator and will take place in the rich academic environment of Stanford University where I will have access to state-of-the-art facilities and be afforded the opportunity to interact with leading cardiovascular scientists and clinicians. The plan encompasses three main areas 1) research (e.g. technical skills, communication), 2) education (e.g. RCR, translational research), and 3) career development (e.g. networking, acquiring K99/R00).
