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Dr. Jared McLendon, Assistant Professor

Department of Pharmaceutical Sciences and Therapeutics, University of Iowa College of Pharmacy

Abstract:

Sorbs2 is a cytoskeletal adapter protein with emerging roles in cardiovascular disease, neurodegeneration, and vascular dysfunction. Using bioinformatics, tissue-specific knockout mouse models and isoform-specific detection tools, our research has revealed that Sorbs2 exhibits extensive isoform diversity with tissue- and cell-type-specific expression patterns that dictate distinct biological functions. In cardiomyocytes, we discovered that Sorbs2 is required for microtubule stability, and genetic knockout impairs contraction and causes dilated heart failure. Conversely, in vascular smooth muscle cells (VSMCs), Sorbs2 localizes primarily to the actin cytoskeleton and cell-cell junctions. VSMC-specific knockout decreases proliferation, dysregulates contractile genes, and unexpectedly increases agonist-induced arterial contractility while decreasing vascular stiffness— opposite to its effects in cardiomyocytes. In the nervous system, we found that Sorbs2 is abundantly expressed in hippocampal neurons, primarily residing in post- synaptic density regions. A genetic variant in the Sorbs2 promoter associates with increased expression and delayed Alzheimer's Disease (AD) onset by 11 years. Sorbs2 expression progressively decreases in AD patient brains and mouse models, particularly in neurons with neurofibrillary tangles. Our behavioral studies in Sorbs2 knockout mice revealed significant deficits in learning and memory, suggesting a protective role against neurodegeneration. Notably, while neurons express a neuron-specific isoform with potential RNA-binding activity, vascular cells within the brain express different isoforms lacking this domain. To advance these studies, we developed extensive research tools including expression plasmids for ~10 isoforms, multiple tissue-specific knockout mouse models (global, cardiomyocyte-specific, smooth muscle-specific, and conditional), validated siRNA reagents, isoform-specific antibodies, and custom RNAscope probes. We have generated comprehensive microRNA binding site maps across human tissues and performed RNAseq in brains, hearts, and arteries. These findings establish Sorbs2 as a critical regulator of tissue-specific cytoskeletal function with therapeutic potential across multiple disease contexts.