Integrating primate-rodent cell types and epigenomics to identify conservation in substance addiction

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Project Summary/Abstract Substance use disorders (SUD) of many highly addictive drugs affect more than 100 million people worldwide. Genetic variations associated with complex neuro-behavioral traits, such as drug addiction, are likely to impact enhancers which have a high degree of cell type-specificity and can be conserved across species. Furthermore, variation in addiction behavior has been linked to genetic variation in both human and rodents. Thus, it follows that genetic mechanisms driving addiction behavior, specifically at cell type-specific enhancers, might also be conserved between primates and rodents. I hypothesize that risk variants for some SUDs may lie in enhancers of distinct cell types in the reward areas and not others, providing insight into the cell types that are critical to SUDs. This project proposes to identify the gene markers and putative enhancers of cell types that are conserved or clade-specific to primates and rodents and of these, which are enriched for SUD human genetic risk variants. The proposal comprises of the following aims: Aim 1: identify the primate-rodent conserved cell types and marker gene profiles enriched for human SUD risk variants. Aim 2: identify the primate-rodent conserved putative enhancer profiles to test whether mouse substance use behavior risk loci disrupt similar putative conserved enhancers to human SUD risk loci. Together, these experiments could reveal primate-rodent gene and enhancer atlas of conserved and species-specific cell types of the reward system by integrating single-nuclei genomics data across multiple mammalian species. This information is critically important because better understanding of how an individual’s genetic makeup could affect the cells of the reward circuit will inform future work to craft personalized, targeted SUD therapy. Thus, this work integrates closely with my clinical interests in addiction medicine. This proposal outlines a combination of rigorous mentored research training, longitudinal clinical experiences, coursework, and professional and leadership development activities. The intellectual, technical, and professional skills refined during this fellowship training period will be instrumental in my development as an aspiring physician scientist in the clinical field of addiction medicine.