Single Cell Foundation Model enabled drug discovery for clonal hematopoiesis

Aging is associated with increased mortality and the prevalence of diseases such as cancer, cardiovascular, neurological, and respiratory diseases. One fundamental mechanism of aging is acquiring DNA mutations, which can lead to clonal hematopoiesis of indeterminate potential (CHIP), frequently driven by mutations in in DNMT3A, TET2, and ASXL 1. We seek to identify and re purpose existing medications or investigational therapeutics to decrease or eliminate the CHIP clone as a way to address multiple agingrelated diseases. We will leverage single cell machine learning foundation models, human genetics, and electronic health records (EHR). We propose a two-phase approach: In the UG3 phase, we will utilize single cell foundation models to perform virtual screens as well as genetic and EHR data to identify existing medications to reverse CHIP pathology. In the UH3 phase, we will experimentally validate drug candidates in in vitro and in vivo CHIP models. Successful execution of this work will rapidly translate findings into the clinic by repurposing FDA-approved medications to mitigate CHIP and its related aging diseases. Project Number: 1UG3AG097155-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Alexander Bick (+2 co-PIs) | Institution: VANDERBILT UNIVERSITY MEDICAL CENTER, NASHVILLE, TN | Award Amount: $1,013,072 | Activity Code: UG3 | Study Section: Special Emphasis Panel[ZRG1 CN-V (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11258269