Exploring Functional Divergence in Human and Chimpanzee Arteries: Implications for Cardiovascular Disease

PROJECT SUMMARY/ABSTRACT Atherosclerotic cardiovascular disease is the leading cause of death worldwide and its rates are rapidly rising, especially in the developing world. Despite decades of research, many questions remain about the disease’s cellular and molecular processes. Chimpanzees, the closest living relative of humans, are not as susceptible to atherosclerosis, despite having higher serum cholesterol levels. This divergence in disease susceptibility between closely related species provides a novel approach to study atherosclerosis. To study these species-specific changes, I will utilize recently published human-chimpanzee hybrid cell lines, a system that allows for the precise detection of species-specific gene expression changes. These cells will be used in conjunction with a protocol that allows for the creation of pure populations of arterial endothelial cells (aECs) from induced pluripotent stem cells. Using the hybrid cells, I have already identified several candidate pathways which exhibit species-specific gene expression changes in aECs. In aim 1, I will assay the function of aECs from both species and identify novel phenotypic differences between human and chimpanzee arterial endothelial cells. These disparities could provide insights into developmental differences as well as provide clues to atherosclerotic mechanisms. Inflammatory signals are thought to drive atherosclerosis and my preliminary data shows differences in gene expression between species following exposure to inflammatory cues. In aim 2, I will identify gene expression divergence between species by subjecting hybrid cells to stimuli that mimic an atherosclerotic environment. By measuring species-specific expression changes in various conditions, I can catalog the genes that are differentially regulated upon exposure to atherosclerotic stimuli, to provide clues about disease pathology. These changes in gene expression will need to be functionally validated to demonstrate that they can influence atherosclerosis susceptibility or progression. In aim 3, I will use pharmacological and genetic methods to interrogate the results from aim 2 to discover novel pathways and genes that influence atherosclerosis. By forming aECs with human, chimpanzee, and hybrid cell lines and dissecting their phenotypes, new insights will be gained into the pathways and genes that are atheroprotective in chimpanzee. Furthermore, my findings will provide a new framework to model the development of atherosclerosis, which may one day be leveraged into novel therapeutic strategies.