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Department of Defense Funds $1.5 Million Grant to Dr. Tarak Srivastava to Study Immunopathogenesis of Nephrotic Syndrome in Children


Department of Defense Funds $1.5 Million Grant to Dr. Tarak Srivastava to Study Immunopathogenesis of Nephrotic Syndrome in Children

Headshot of Tarak Srivastava, MD, FASN
Tarak Srivastava, MD, FASN
Director, Osteogenesis Imperfecta Program; Director, Nephrology Research Laboratory; Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Education Associate Professor of Pediatrics, University of Kansas School of Medicine
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Tarak Srivastava, MD, FASN, Nephrology, has been awarded a FY23 Peer Reviewed Medical Research Program (PRMRP) Investigator-Initiated Research Award from the Department of Defense’s Congressionally Directed Medical Research Programs. The grant will support his project from September 1, 2024, through August 31, 2028, with a total award amount of $1,552,348. Mukut Sharma, PhD, at Kansas City VA Medical Center, a long-time collaborator of Dr. Srivastava, will receive $1,209,369 as a partnering-PI on this project.

“Nephrotic syndrome is a major medical, social, and economic problem,” says Dr. Srivastava, acknowledging the significance of the research.

The funding supports Dr. Srivastava’s study, “SH3BP2-Mediated Immune Activation Plays a Key Role in Immunopathogenesis of Nephrotic Syndrome.” 

Nephrotic syndrome is a common kidney disease in children that causes protein loss from the blood into the urine leading to proteinuria from damage to the kidney filter. Treatment involves steroids and other immunosuppressive drugs, but it remains empirical due to a lack of understanding of the immune dysregulation of the disease. Patients' quality of life is often poor, and some progress to end-stage kidney disease, requiring dialysis or transplantation.

Dr. Srivastava explains that recent studies with human genetic data have shown significantly increased gene expression levels of a protein called SH3BP2 and its associated binding proteins in kidney biopsies of patients with nephrotic syndrome. Human podocytes, which are crucial components of the glomerular filtration barrier that are damaged in nephrotic syndrome, express the SH3BP2 protein. SH3BP2 serves as a binding scaffold for other proteins that regulate immune signaling pathways, making it a master regulator of immune mechanisms. Dr. Srivastava and his team have developed a genetically modified strain of mice (Sh3bp2KI/KI) that leads to marked immune activation from active Sh3bp2, resulting in the animals developing all the characteristic features of human nephrotic syndrome.

This project builds on Dr. Srivastava and Dr. Sharma's published work titled "Scaffold protein SH3BP2 signalosome is pivotal for immune activation in nephrotic syndrome. JCI Insight. 2024:e170055," which describes human biopsy data and transgenic mice. The investigators have always been intrigued by how the immune system causes structural changes in cells, leading to kidney filter damage and protein loss in urine. This study aims to investigate how the scaffold protein SH3BP2, along with its binding partners VAV2 and PLCG2, contributes to both innate and adaptive immune activation, playing a central role in nephrotic syndrome's pathogenesis. Dr. Srivastava and his team hypothesize that immune-mediated injury and structural damage to podocytes in nephrotic syndrome are mediated by downstream signaling involving SH3BP2-PLCG2 and SH3BP2-VAV2.

Dr. Srivastava has also been awarded a one-year $25,000 grant through the Institute for Advancing Medical Innovation (IAMI) Trailblazer Award from Frontiers Clinical & Translational Science Institute (CTSI) for his project titled "SH3BP2 inhibitors to target SH3BP2-mediated immune activation in nephrotic syndrome." The project began on July 1, 2023, and will continue through June 30, 2024. In this study, the team aims to identify small molecules as candidate inhibitors of SH3BP2 and validate them using cell culture and mouse models.

“Our long-term goal is to understand the process of disease development in nephrotic syndrome and develop targeted therapy with an SH3BP2 inhibitor to replace empirical treatment,” said Dr. Srivastava.

Other co-investigators on the project include John Perry, PhD, and Emily Farrow, PhD, at Children’s Mercy Kansas City and Wenjun Ju, PhD, and Viji Nair, PhD, of the University of Michigan.

Funding Support:

This work was supported by The Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, in the amount of $1,552,348.00 and $1,209,369.00 through the Peer Reviewed Medical Research Program under Award Numbers HT9425-24-1-0235 and HT9425-24-1-0236. Opinions, interpretations, conclusions, and recommendations are those of the author(s) and are not necessarily endorsed by The Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense.