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Understanding Polycystin-1 Structure-GPCR Function for the Development of New Therapeutic Approaches in ADPKD

Award Number: R01DK123590
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Summary Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal genetic disease. Eighty-five percent of the cases of ADPKD are due to mutation of the PKD1 gene of which approximately ¼-1/3 are due to missense mutations and small, in-frame deletions that may be amenable to functional rescue. PKD1 encodes polycystin-1 (PC1), a large and complex protein thought to function as an atypical G protein-coupled receptor (GPCR). The loss of PC1-G protein regulation is now known to be fundamental to the pathogenesis of PKD, yet we know essentially nothing about the mechanism whereby PC1 regulates G protein signaling activity. Our long-term goal is to understand the mechanism underlying PC1-G protein regulation in order to target and functionally restore or augment this function as a treatment for ADPKD. Based on the structural and functional similarities between PC1 and the adhesion class of GPCRs, and intriguing results from our preliminary studies, we propose that a mechanism involving a cryptic tethered peptide ligand is responsible for the regulation of G protein signaling by PC1, and furthermore, is involved in the pathogenesis of renal cyst formation. The major goals of this proposal, therefore, are to determine the structure-function relationships behind the tethered ligand-mediated regulation of G protein signaling by PC1 and to demonstrate the relevance of this regulatory mechanism in the pathogenesis and potential treatment of ADPKD. Specifically, we intend to determine the essential properties of the tethered peptide ligand of PC1 responsible for its regulation of G protein signaling, map the regions of PC1 involved in tethered ligand- dependent signaling, and determine the conditions for the peptide ligand-dependent rescue of renal cystogenesis. The proposed studies will employ transfection of established cell lines along with standard molecular biology methods and biochemical assays to assess the signaling capability of modified expression constructs of PC1 and of soluble tethered ligand-derived peptides, and will include the treatment of cystic kidneys with soluble tethered ligand-derived peptides in both ex vivo and in vivo model systems. Successful completion of this project is expected to reveal molecular details of the regulation of G protein signaling by PC1 via its cryptic, tethered ligand, and to demonstrate the potential of this regulatory mechanism as a novel therapeutic target. Elucidating the mechanism of PC1-regulated G protein signaling will advance our understanding of the molecular pathogenesis of ADPKD, which is imperative for the development new therapies for the treatment or prevention of this 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: 2023 ( Subtotal = $336,600 )
2023	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/6/2022	NON-COMPETING CONTINUATION	$302,940
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	001	4	1/6/2023	NON-COMPETING CONTINUATION	$33,660
														Subtotal = $336,600

Issue Date FY: 2022 ( Subtotal = $336,600 )
2022	2022	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/31/2022	NON-COMPETING CONTINUATION	$33,660
2022	2022	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/4/2021	NON-COMPETING CONTINUATION	$302,940
														Subtotal = $336,600

Issue Date FY: 2021 ( Subtotal = $327,738 )
2021	2021	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/2/2021	NON-COMPETING CONTINUATION	$32,774
2021	2021	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/1/2020	NON-COMPETING CONTINUATION	$294,964
														Subtotal = $327,738

Issue Date FY: 2020 ( Subtotal = $472,037 )
2020	2020	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	8/31/2020	SUPPLEMENT FOR EXPANSION	$149,429
2020	2020	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/14/2020	NEW	$322,608
														Subtotal = $472,037

Grand Total All Awards = $1,472,975

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Understanding Polycystin-1 Structure-GPCR Function for the Development of New Therapeutic Approaches in ADPKD

Award Number: R01DK123590

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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