Biological function of testican-2 in podocyte health

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PROJECT SUMMARY/ABSTRACT Using a proteomic screen of samples obtained from the aorta and renal vein of human subjects, we recently identified testican-2 as a podocyte-derived protein that is released by the kidney into circulation. Further, we found that testican-2 levels are positively correlated with estimated glomerular filtration rate (eGFR) and higher baseline levels of testican-2 are associated with less eGFR loss over time, advancing the concept that testican-2 provides insight on kidney health and prognosis. However, the biological function of testican-2 in podocytes and the kidney is unknown. Encoded by the SPOCK2 gene, testican-2 is a glycoprotein that is a component of the extracellular matrix (ECM). In preliminary data generated by the PI, we find that testican-2 attenuates podocyte injury induced by Adriamcyin both in cultured human podocytes and mice. We further find that testican-2 binds to another ECM protein vitronectin and reduces its binding affinity to integrin αVβ3, an adhesion protein on the podocyte surface. Using these findings as a springboard, this proposal will test the central hypothesis that testican-2 plays a functional role in podocyte health by reducing vitronectin-mediated integrin αVβ3 activation and signaling: Aim 1) To determine the protein domain required for testican-2 binding with vitronectin; Aim 2) To determine the impact of testican-2 on integrin αVβ3 activation and podocyte injury; and Aim 3) To assess testican-2 expression in patients with diabetic nephropathy and primary focal segmental glomerulosclerosis. The candidate, Dr. Wen, is deeply committed to a career in academic nephrology. He previously pursued broad-based research training in nephrology, with a particular focus on renal physiology. Since pursuing a nephrology fellowship in 2018, he has shifted his focus to a new area—the biological function of testican-2 in podocyte health, with both basic and translational approaches. Dr. Wen’s immediate career goals include acquiring content knowledge and hands-on experience with emerging technologies in the areas of podocyte biology; protein-protein interaction and structure; and blood and tissue biomarkers. In addition, he seeks training with public speaking and grant and manuscript writing. Dr. Wen’s long-term career goal is to become an independent physician-scientist who pursues both basic and translational approaches to develop new therapeutic strategies for patients with podocytes injury, and kidney disease in general. He will benefit from complementary mentorship from Eugene Rhee (mentor; Chief, MGH Nephrology), an expert in kidney metabolism and biomarkers; and Martin Pollak (co-mentor, Chief, BIDMC Nephrology), a leader in genetics and podocyte biology. Drs. Wen, Rhee, and Pollak will meet frequently to discuss both science and career development and have clearly identified aspects of the research proposed that will form the basis of his independent career. An advisory committee will provide additional guidance, evaluate progress, and help plan future directions.