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NPHP2 in ciliary function, renal fibrosis and cyst formation

Award Number: R01DK113135
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: 09/15/2017
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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NPHP2 in ciliary function, renal fibrosis and cyst formation - This proposal focuses on both cell autonomous and non-autonomous function of the nephronophthisis (NPHP) gene, Nphp2, in renal fibrosis and cyst formation. NPHP is a recessive renal ciliopathy characterize by interstitial fibrosis and cysts. Although NPHP accounts for a significant portion of end stage renal disease in children and young adults, currently no targeted therapy is available for this disease and the underlying molecular etiology, particular for interstitial fibrosis, is not well understood, even though NPHP proteins have been put into different modules biochemically. The lack of knowledge hampers the effort to develop targeted therapy for this disease. Previous work showed that mouse whole-body knockout model of Nphp2 displays renal fibrosis and cysts at the neonatal stage. By generating and analyzing epithelial and complementary stromal specific knockout mouse models of Nphp2, we pinpointed defective epithelial cells as the driver for both interstitial fibrosis and epithelial cyst formation. In addition, myofibroblast activation occurred early during disease progression and preceded detectable cyst formation in the epithelial specific Nphp2 mutants. Moreover, abrogation of cilia genetically partially suppresses the phenotype of Nphp2 mutants, suggesting that cilia play a significant role in Nphp2 function. The central hypothesis of this project is that Nphp2 inhibits a cilia-dependent profibrotic and pro-cystic pathway in renal epithelial cells and that both cell autonomous and non-autonomous responses contribute to disease progression. Two specific aims were proposed to test this hypothesis. Aim 1 focuses on renal epithelial cells. A combination of approaches, from in vivo phenotype characterization, transcriptome profiling to pathway analysis to identify key pathways that are disrupted in Nphp2 mutant epithelial cells. Aim 2 focuses on epithelial-interstitial crosstalk and will determine how stromal cells respond to epithelial cells with defective NPHP2 and whether stromal cells modify phenotypes of Nphp2 mutants. Completion of this project will provide critical insight into the molecular and cellular etiology of NPHP and cilia-mediated signaling under diverse physiological and disease states.


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 = $586,989 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	4/7/2026	NON-COMPETING CONTINUATION	$586,989
														Subtotal = $586,989

Issue Date FY: 2025 ( Subtotal = $614,552 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	4/22/2025	NON-COMPETING CONTINUATION	$614,552
														Subtotal = $614,552

Issue Date FY: 2024 ( Subtotal = $589,970 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	7	5/17/2024	NON-COMPETING CONTINUATION	$589,970
2024	2023	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	3/26/2024	COMPETING CONTINUATION	$47
2024	2021	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/26/2024	NON-COMPETING CONTINUATION	-$47
														Subtotal = $589,970

Issue Date FY: 2023 ( Subtotal = $586,989 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	6/19/2023	COMPETING CONTINUATION	$586,989
														Subtotal = $586,989

Issue Date FY: 2021 ( Subtotal = $376,875 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/11/2021	NON-COMPETING CONTINUATION	$376,875
														Subtotal = $376,875

Issue Date FY: 2020 ( Subtotal = $376,875 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/30/2020	NON-COMPETING CONTINUATION	$376,875
														Subtotal = $376,875

Issue Date FY: 2019 ( Subtotal = $376,875 )
2019	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/29/2019	NON-COMPETING CONTINUATION	$376,875
														Subtotal = $376,875

Issue Date FY: 2018 ( Subtotal = $376,875 )
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/31/2018	NON-COMPETING CONTINUATION	$376,875
														Subtotal = $376,875

Issue Date FY: 2017 ( Subtotal = $376,875 )
2017	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/21/2017	NEW	$376,875
														Subtotal = $376,875

Grand Total All Awards = $4,262,875

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NPHP2 in ciliary function, renal fibrosis and cyst formation

Award Number: R01DK113135

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: 09/15/2017

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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