Faculty Affairs and Academic Programs
Arun Padmanabhan
Medical; Health Sciences; Nursing
Unraveling Cardiac GWAS Mechanisms with in vivo CRISPR Screening
Heart failure and cardiomyopathy remain leading causes of death worldwide, yet the molecular mechanisms linking genetic risk variants to disease remain largely unknown. While genome-wide association studies (GWAS) have identified hundreds of loci associated with cardiac traits, most candidate genes have not been functionally validated due to technical challenges of manipulating mature cardiomyocytes in vivo. This proposal overcomes these barriers by developing an in vivo CRISPR-based single-cell functional genomics platform to interrogate cardiac GWAS signals in adult mouse hearts. Using adeno-associated viral (AAV9) vectors engineered for cardiomyocyte specificity, we will deliver dual guide RNAs targeting 200 genes prioritized from multi-trait GWAS analyses of left ventricular structure and function. By integrating magnetic enrichment of transduced nuclei with single-nucleus RNA sequencing, this approach directly links each gene perturbation to its transcriptional signature within native tissue. This platform represents a transformative step in cardiovascular genetics, enabling high-resolution mapping of gene function in a physiologically relevant model. Results will identify key regulatory networks driving ventricular remodeling and heart failure, informing precision therapeutic development. As an early-career physician-scientist in genetic cardiomyopathies, I will leverage this award to establish an independent research trajectory bridging human genomics and in vivo biology. Support from the UC Office of the President will catalyze this next-generation platform, positioning my lab at the forefront of functional cardiovascular genomics.
