Stanford Cardiovascular Institute Seed Grants

Project Description: Mitochondrial diseases (MD) are highly penetrant genetic disorders that result in abnormal intracellular bioenergetic production. Pathogenic mutations in the mitochondrial DNA (mtDNA) are heteroplasmic, where wildtype mtDNA co-exists with the pathogenic mtDNA, and a functional defect is only observed when the pathogenic mtDNA percentage surpasses a threshold for biochemical manifestations. The treatment for MD, however, is currently limited to symptomatic management. There is no curative strategy that reduces the percentage of pathogenic mtDNA below its clinical threshold. We demonstrated that induced pluripotent stem cells (iPSCs) secrete mitochondria-containing extracellular vesicles (EVs). This proposed research aims to investigate whether the EV-mediated replenishment of mitochondria improves mtDNA heteroplasmy, energy metabolism, and systemic phenotypes in a mouse model of MD and obtain preclinical proof-of-concept of mitochondrial transplantation therapy for MD patients.

Project description: Coronary artery disease is the leading cause of death worldwide. Smooth muscle cells make up the bulk of coronary vascular wall and a significant portion of CAD attributable risk resides in the SMC population of cells in the diseased vessel wall. Endoplasmic reticulum (ER) stress has been previously reported to have an adverse impact on vascular smooth muscle cells, atherosclerotic burden and lesion calcification. We observed that under atherogenic conditions, there is increased ER stress and protein aggregation in the coronary SMC population. Previous studies utilizing ER stress inhibitors have shown that targeting ER stress maybe protective against disease progression, however, how ER stress and protein misfolding can drive the disease process is unknown. In this study, we will explore in depth the protein misfolding process in SMC as well as systemically dissect the UPR pathway using Crispr sgRNA library to understand the downstream pathways leading to pathogenic SMC modulation. 

Project description: Dilated Cardiomyopathy (DCM)-associated heart failure is a major cause of death and is characterized by a loss of heart muscle cell contractility. Francesca Briganti, PhD in the Mercola lab has completed a comprehensive functional screen of the human genome and identified nearly 120 genes that, when inhibited, will ameliorate the contractile deficit in human induced pluripotent stem cell (iPSC) models of the disease. The CVI Seed award will fund the next step in translating this discovery to treatment by defining druggable targets among the genes and their interacting partners.

Project Description: The National Health Assessment and Nutrition Examination Survey (NHANES), the National Health Interview Survey (NHIS), and the Behavioral Risk Factor Surveillance System (BRFSS) are three nationally representative datasets that provide complementary, but comprehensive health information used to track and monitor the health of the U.S. population. Previous studies have emphasized that estimates provided by these datasets are similar at the national level, but less so for specific subgroups of U.S. population. This pilot project will examine the robustness and replicability of racial and ethnic disparities in cardiovascular disease (CVD) within the NHANES, NHIS, and BRFSS using multiple imputation techniques. We will also examine the extent to which self-reported measures of CVD from NHIS and BRFSS align with biomarker and clinical indicator measures of CVD in NHANES.