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Uromodulin polymerization and peptides as novel targets in kidney stone pathogenesis

Award Number: R01DK148878
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: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Uromodulin polymerization and peptides as novel targets in kidney stone pathogenesis - Project Summary/Abstract Kidney stones are a painful health problem occurring in 8-12% of the population and accounting for an annual health cost of >$10 billion in the United States. Most kidney stones are composed of calcium oxalate (CaOx). Current therapies to prevent CaOx kidney stones have low efficacy, and recurrence rates are high. Pet dogs naturally form CaOx kidney stones and share many clinical characteristics with human stone formers. In dogs, we discovered a genetic variant in the canine uromodulin gene that has a profound effect on CaOx stone risk. Uromodulin (aka Tamm-Horsfall protein) is the most abundant protein secreted in urine and has long been implicated in human kidney stone risk. However, the precise pathways connecting uromodulin and human kidney stone disease are incompletely defined. Our preliminary work demonstrated that the canine stone-risk variant greatly reduces uromodulin polymerization and alters bioactive uromodulin peptides. These results implicate uromodulin polymerization status and peptides in stone pathogenesis. Our overarching objective is to identify renal cellular and molecular mechanisms through which uromodulin polymerization status and peptides promote CaOx kidney stones. The proposed study will test the hypothesis that uromodulin polymerization status and peptides regulate the activity of key renal solute transporters/channels (Aim 1) and the renal inflammatory response to crystallization (Aim 2). It will also identify abnormalities in urinary uromodulin polymerization status and peptide excretion in human idiopathic CaOx kidney stone formers relative to healthy, age-/sex-matched, stone-free controls with integration of genetic data on uromodulin gene variants (Aim 3). The results of this work will determine how uromodulin polymerization status and peptides impact renal calcium transport and inflammatory molecules involved in crystallization. Uromodulin features, including polymerization and peptide excretion, can be modified with diet or drugs. Thus, the proposed research might result in future development of therapies to enhance the protective function of uromodulin and mitigate risk for stone recurrence in humans with CaOx stones, potentially regardless of their etiology. The work in human CaOx kidney stone formers also has potential to result in novel clinical biomarkers for stone disease or risk.


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 = $821,457 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/28/2026	NEW	$821,457
														Subtotal = $821,457

Grand Total All Awards = $821,457

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Uromodulin polymerization and peptides as novel targets in kidney stone pathogenesis

Award Number: R01DK148878

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: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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