Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Our R01 project will examine the molecular mechanisms underlying environmental exposure-induced telomere damage on mitochondrial function and cellular senescence in cardiac disease. Environmental insults have long been associated with oxidative telomere damage and heart disease. This project seeks to move the field beyond an association and determine the causative role of telomere damage in promoting early onset of age-related cardiac dysfunction. Traditionally, telomere shortening has been studied to explain proliferative exhaustion. However, this is inadequate to explain aging and disease of a largely post-mitotic tissue, such as the heart. Telomere associated foci (TAFs) or DDR+ telomere foci have been reported in multiple cell types of the heart, including cardiomyocytes (CMs) and cardiac fibroblasts (CFs). Our preliminary data shows that telomere-driven senescence is linked to oxidative stress but not telomere shortening, suggesting that oxidative damage contributes to the DDR+ of telomeres and senescence observed in cardiac tissue. A prior lack of tools to induce oxidative damage in a spatial and temporal manner severely limited the ability to understand how such telomere damage contributes to cardiac disease. Now, we have developed an innovative chemoptogenetic tool that produces oxidative damage, 8-oxoguanine (8-oxoG) lesions, specifically at telomeres, thus mimicking environmentally induced telomere damage. Another critical barrier in understanding the cell autonomous versus non-autonomous role of telomere damage in a complex tissue like the heart was the lack of a platform to introduce telomere damage in one cell type (e.g., CM) and examine its effect on another (e.g., CF), and on cardiac function. We have now also developed tools that enable the study of cell-cell communication in a 3D multicellular system, allowing us to reproduce tissue dynamics present in the heart. We will test the hypothesis that oxidative damage at telomeres in specific cardiac cell types leads to mitochondrial dysfunction, senescence, and release of paracrine factors, thus contributing to electrophysiological changes and heart disease. We will induce oxidative telomere damage specifically in induced pluripotent stem cell (iPSC)-derived CMs and CFs to explore three aims: (1) map how oxidative telomere damage communicates with mitochondria to drive a biological outcome- senescence; (2) define the cell non-autonomous role of telomere damage in the heart; and (3) examine the molecular role of repair at telomeres in cardiac health. Our team is uniquely qualified to perform this work, with expertise in telomere damage/repair, mitochondrial assessments, cellular senescence, nanofabrication, and human iPSC-derived cardiac tissue engineering. This project is highly significant because it will allow us to gain a more comprehensive understanding of the role of environmental driven telomere status on cardiac health, which will lead to the discovery of promising new therapeutic targets.
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).