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Mechanisms of cyst progression driven by Na,K-ATPase in autosomal dominant polycystic kidney disease (ADPKD).

Award Number: F30DK137438
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/04/2024
PERIOD OF PERFORMANCE END DATE: 08/03/2028

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Mechanisms of cyst progression driven by Na,K-ATPase in autosomal dominant polycystic kidney disease (ADPKD). - Project Summary/Abstract Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the growth of fluid-filled cysts that disrupt the renal architecture and function, leading to end-stage renal disease (ESRD), dialysis, and renal transplantation. Although ADPKD has a genetic origin, its progression and clinical outcome is highly variable and dependent on agents circulating in blood. Previous work from our laboratory has shown that one of these agents is ouabain. In primary renal epithelial cells obtained from kidneys of patients with ADPKD, ouabain promotes the cystic phenotype by increasing cell proliferation, augmenting cAMP-dependent fluid secretion, and inducing cell dedifferentiation; ouabain also stimulates cyst progression in embryonic renal explants and adult kidneys of ADPKD mouse models. Ouabain exerts these effects via its cell plasma membrane receptor, Na,K-ATPase (NKA), through the activation of signal transduction pathways in the cell. Ouabain also inhibits the exchange of Na+ for K+ across the cell plasma membrane characteristic of NKA ion transport function, which contributes to reduce fluid reabsorption in the renal epithelium and enhance ADPKD cyst progression. While all NKA appears to function as an ion transporter, it is believed that the NKA residing in caveolae is involved in ouabain-induced signal transduction. In caveolae, NKA forms a complex with other proteins in what is known as the “NKA signalosome”; key to this receptor complex is the association of NKA with the kinase Src, which allows NKA to function as a tyrosine kinase-coupled receptor. At present, the mechanisms by which the NKA signalosome functions in ADPKD are unknown. Moreover, it is unclear if ouabain affects both the signaling and ion transport functions of NKA to drive ADPKD cystogenesis. I hypothesize that elimination of NKA signaling capacity, through caveolar depletion or disruption of NKA/Src interaction, will reduce ouabain- induced ADPKD cyst progression. Aim 1 will determine the role of caveolae in ouabain-induced NKA signaling and ADPKD cyst progression. The role of caveolae in ADPKD is currently unknown; I will use a novel mouse model to determine necessity of caveolae for ouabain's effects in ADPKD cyst progression and NKA signaling. Aim 2 will establish NKA/Src interaction as the mechanism driving ouabain effects in ADPKD. The mechanisms involved in the activation of the NKA signalosome are currently unknown. I will create a novel mouse model which interrupts the NKA/Src binding site and determine how the absence of this interaction affects ADPKD cyst progression and NKA signal transduction. Completion of these aims will give a better understanding of how ouabain accelerates ADPKD cyst growth and characterize a novel mechanism of cyst progression which can be targeted to develop future therapeutics for the treatment of ADPKD. The training plan outlined in this fellowship will not only develop my technical research skills, but also provide both clinical and research mentorship, opportunities for teaching, and a carefully planned transition back to medical school.


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 = $58,114 )
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	3	7/6/2026	NON-COMPETING CONTINUATION	$58,114
														Subtotal = $58,114

Issue Date FY: 2025 ( Subtotal = $40,280 )
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	2	6/30/2025	NON-COMPETING CONTINUATION	$40,280
														Subtotal = $40,280

Issue Date FY: 2024 ( Subtotal = $37,313 )
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	1	7/24/2024	NEW	$0
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	1	7/24/2024	NEW	$37,313
														Subtotal = $37,313

Grand Total All Awards = $135,707

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Mechanisms of cyst progression driven by Na,K-ATPase in autosomal dominant polycystic kidney disease (ADPKD).

Award Number: F30DK137438

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/04/2024

PERIOD OF PERFORMANCE END DATE: 08/03/2028

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