Project Summary Derangement of metabolic pathways involved in cellular lipid metabolism1 and ER stress2 have been shown to contribute to the pathogenesis of chronic kidney disease (CKD). We3-6 and others7 demonstrated that ATP- binding cassette transporter A1 (ABCA1) deficiency contributes to podocyte injury and disease progression of glomerular diseases of metabolic and non-metabolic origin. While ABCA1 deficiency is insufficient to cause podocyte injury, in vitro or in vivo, and proteinuria despite causing impaired cholesterol efflux and mitochondrial dysfunction5, overexpression of ABCA1 or pharmacological induction of ABCA1 (ABCA1i)5 was sufficient to rescue glomerular injury in proteinuric mice. Proximity labeling followed by immunoprecipitation of transfected potential targets led to identifying oxysterol binding to oxysterol-binding protein (OSBP) like 7 (OSBPL7) as the target of ABCA1i8. OSBPL7 is a member of a group of lipid-binding proteins involved in the movement of lipids between membranes8. OSBPs play a role in initiating autophagy9, cholesterol transfer from the endoplasmic reticulum (ER) to the Golgi, cholesterol efflux, and regulating ABCA1 expression10. However, if OSBPL7 is expressed in the kidney and if it is involved in regulating ABCA1-mediated cholesterol efflux or in the preservation of ER function in the podocyte has not been explored. The proposed research will investigate the function of OSBPL7 in podocytes. Based on my preliminary data, I hypothesize that OSBPL7 deficiency causes ABCA1-dependent impairment of cholesterol efflux and ABCA1- independent ER stress, thus linking OSBPL7 to podocyte injury and CKD progression. I propose the following specific aims using in vitro and in vivo approaches: (SA1) In vitro, determine the role of OSBPL7 in modulating ABCA1-dependent functions in podocytes. (SA2) In vitro, determine the mechanism by which OSBPL7 deficiency contributes to ER stress independent of ABCA1. (SA3) In vivo, determine if restoring renal OSBPL7 levels is sufficient to preserve renal function in col4a3 depleted zebrafish. I have created a comprehensive career development plan supported by my mentor and co-mentor to ensure my progress and success in this research proposal and facilitate my transition to an independent research career focused on lipid metabolism in association with glomerular disease. This plan includes (1) regular meetings with my mentor, co-mentors, and advisory committee, to provide research and career guidance, (2) research and career development seminars, learning new research methodologies, and (3) activities for career growth, including mentoring, publication, presentation, and application for independent research funding. My training will be conducted in an unparalleled academic environment at the University of Miami, Miller School of Medicine, which provides dedicated career development programs and necessary research support and supplies through my mentor, co-mentors, and institutiona...