Project Grant R03DK144350

The National Institute of Diabetes and Digestive and Kidney Diseases awarded The Ohio State University $118,125 on July 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847, Project Grant R03DK144350).

The award funds research into the mechanisms by which APOL1 kidney risk variants G1 and G2 drive chronic kidney disease in podocytes, with focus on peroxisomal dysfunction as a mediator of variant-associated cytotoxicity. The research team performed a genome-wide siRNA screen that identified acyl-CoA oxidase 1 (ACOX1), a fatty acid oxidation enzyme, as a critical driver of APOL1 variant toxicity under hypoxic and inflammatory stress. Experimental evidence demonstrates that hypoxia increases APOL1 expression, triggers translocation to peroxisomes where G1/G2 variants bind ACOX1 more strongly than the G0 wild-type, accelerates peroxisomal fatty acid oxidation, and generates excess reactive oxygen species. Kidney biopsies from APOL1 high-risk focal segmental glomerulosclerosis patients show increased glomerular ACOX1 expression consistent with this mechanism. Aim 1 will define how ACOX1 overexpression, gain- or loss-of-function mutations, and APOL1-ACOX1 interaction shape variant-specific injury in human podocytes and validate findings in APOL1-genotyped human kidney biopsies. Aim 2 will test whether pharmacologic ACOX1 inhibition using 10,12-tricosadiynoic acid restores peroxisomal homeostasis and reduces APOL1-variant toxicity in podocytes and APOL1 transgenic mice subject to interferon-gamma stress.

Performance is conducted in Columbus, Ohio, with a period of performance through June 30, 2028.