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Structural and Functional Mechanisms of Podocin in Glomerular Membrane Organization and Kidney Disease

Award Number: R01DK146938
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/23/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Structural and Functional Mechanisms of Podocin in Glomerular Membrane Organization and Kidney Disease - Project Summary/Abstract Steroid-resistant nephrotic syndrome is a devastating pediatric kidney disorder characterized by proteinuria, glomerulosclerosis, and progression to end-stage renal failure. A significant fraction of childhood-onset SRNS cases are caused by mutations in NPHS2, which encodes Podocin—a membrane scaffolding protein essential for maintaining the integrity of the glomerular filtration barrier. Despite Podocin’s critical role in kidney function, its molecular architecture, assembly mechanisms, and the structural consequences of disease-causing mutations remain unknown. This gap in knowledge hinders the development of targeted therapies for steroid-resistant nephrotic syndrome. This project aims to determine the structural organization and mechanistic function of Podocin in native membranes and to identify strategies to restore its activity in disease contexts. We will apply a detergent- free, vesicle-based cryo-electron microscopy platform—developed by our group—to resolve the full- length structure of Podocin at near-atomic resolution. Building on recent breakthroughs in visualizing related SPFH-domain proteins, including Flotillin and Stomatin, we hypothesize that Podocin assembles into higher-order oligomers that scaffold signaling domains at the slit diaphragm. Using cryo-EM, site- directed mutagenesis, and functional assays, we will determine how steroid-resistant nephrotic syndrome-associated mutations disrupt Podocin oligomerization, membrane targeting, and function. In parallel, we will develop a structure-guided discovery pipeline to identify therapeutic strategies that rescue defective Podocin variants. This includes high-content imaging assays, DNA-encoded library screening for small-molecule stabilizers, and de novo peptide design targeting key oligomerization interfaces. Candidate rescue agents will be validated structurally and functionally in cell models and podocyte systems. This interdisciplinary project integrates structural biology, membrane biophysics, kidney cell biology, and drug discovery to address an urgent unmet need in pediatric nephrology. The outcomes will provide foundational insights into the molecular basis of steroid-resistant nephrotic syndrome, define new principles of membrane domain organization, and pave the way for the development of targeted therapeutics for patients with NPHS2-linked kidney disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $388,750 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/27/2026	NEW	$388,750
														Subtotal = $388,750

Grand Total All Awards = $388,750

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Structural and Functional Mechanisms of Podocin in Glomerular Membrane Organization and Kidney Disease

Award Number: R01DK146938

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/23/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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