Probing mechanistic links between endothelial aging and dementia - PROJECT SUMMARY The mission of our laboratory is to pursue answers to essential questions in the field vascular aging that will advance our basic understanding and translate into more effective treatments to optimize human vascular healthspan. The central thesis of this project is that endothelial cells differentiated from hiPSCs, obtained from a diverse group of healthy adults and those with vascular contributions to cognitive impairment and dementia (VCID), can be leveraged to study endothelial aging in dementia. Using a computational model to identify biosignatures that predict endothelial cell aging, we will leverage this information to probe mechanisms relevant to dementia. Our research bridges the fields of vascular biology, stem cell biology, epigenetic clocks, multi -omics, and computational modeling to close the gap in the availability of models for the study of endothelial aging in dementia. There is a tremendous opportunity to address outstanding questions in this field using the novel human induced PlurIPotent stem cell-endothELIal cell model of aging for the study of vascular coNtributIoNs to coGnitive impairment and dementia (PIPELINING) described in this application. We will (1) passage human induced pluripotent stem cells differentiated to endothelial cells (hiPSC-ECs) and identify aging endpoints modeled in vitro (mitochondrial function, senescence, and angiogenesis). (2) A computational multi-scale model will be developed to predict the aging endpoints using multi -omic biosignatures for each human donor and passage. (3) Biosignature covariates judged to be critical contributors to the PIPELINING model will be selected for further mechanistic study. Achievement of the PIPELINING model would represent a significant advance in the application of contemporary technologies (iPSCs, epigenetic clocks, -omics, computational multi-scale modeling) to VCID.
