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Pathogenic reciprocal interplay between cyst epithelium and myofibroblasts in polycystic kidney disease

Award Number: R01DK135308
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: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Pathogenic reciprocal interplay between cyst epithelium and myofibroblasts in polycystic kidney disease - PROJECT SUMMARY/ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is an inherited kidney disease. The goal of this study is to determine if renal interstitial myofibroblasts play an essential role in ADPKD progression by undergoing autophagy and supplying nutrients that support cyst growth. While myofibroblasts are known to be important for renal fibrosis, our novel preliminary data suggests that myofibroblasts could directly regulate cyst growth in ADPKD kidneys by paracrine mechanisms. We found that secreted factors from cyst epithelial cells such as lactate, stimulate autophagy in myofibroblasts by a hypoxia-inducible factor (HIF1α)- dependent mechanism. Moreover, factors such as glutamine, secreted by ADPKD renal myofibroblast- by a HIF1α and autophagy dependent mechanism increased proliferation and cyst growth of human ADPKD cyst epithelial cells. Hence, we hypothesize that, cyst epithelial cells use paracrine mechanisms to induce autophagy in myofibroblasts, leading to secretion of cyst-growth promoting factors. Aim 1 will test if reducing the renal myofibroblast population will reduce cyst growth in mouse ADPKD kidneys. Aim 2 will determine the role of myofibroblast-specific HIF1α in cyst growth. In Aim 3, the role of myofibroblast-specific autophagy and metabolites secreted by myofibroblasts in cyst-expansion will be examined. In addition to the innovative hypothesis, our studies will use state of the art transgenic and tissue specific gene knockout mice and identify myofibroblast -specific secreted factors, important for regulation of cyst growth in ADPKD kidneys. These studies are significant because we test a novel and fundamental mechanism by which cyst epithelial cells manipulate myofibroblasts in their microenvironment to produce nutrients to support cyst growth and disease progression in ADPKD. Although altered metabolism, hypoxia, autophagy, and the role of the cyst microenvironment in cyst growth are emerging fields in ADPKD pathophysiology, the importance of myofibroblast-mediated regulation of cyst growth is unclear. This study will build on our lab's strengths in studying ADPKD pathophysiology, with co-investigators and collaborators who are leaders in the fields of PKD, hypoxia, metabolism or autophagy. The results are expected to lead to development of better therapies for ADPKD.


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 = $474,542 )
2026	2026	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/15/2025	NON-COMPETING CONTINUATION	$474,542
														Subtotal = $474,542

Issue Date FY: 2025 ( Subtotal = $433,227 )
2025	2025	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/21/2024	NON-COMPETING CONTINUATION	$433,227
														Subtotal = $433,227

Issue Date FY: 2024 ( Subtotal = $466,037 )
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/10/2024	NON-COMPETING CONTINUATION	$29,127
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/2/2023	NON-COMPETING CONTINUATION	$436,910
														Subtotal = $466,037

Issue Date FY: 2023 ( Subtotal = $506,706 )
2023	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/30/2023	NEW	$506,706
														Subtotal = $506,706

Grand Total All Awards = $1,880,512

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Pathogenic reciprocal interplay between cyst epithelium and myofibroblasts in polycystic kidney disease

Award Number: R01DK135308

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: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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