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Mechanisms mediating podocyte-parietal epithelial cell crosstalk in proliferative glomerulopathies

Award Number: R01DK121846
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: 09/14/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Mechanisms mediating podocyte-parietal epithelial cell crosstalk in proliferative glomerulopathies - To date, approximately 30 million Americans are estimated to have chronic kidney disease, a major health care burden in the United States. Podocytes are terminally differentiated post-mitotic visceral epithelial cells in the glomerulus whose major function is the maintenance of the renal filtration barrier. Glomerular diseases such as Rapidly Progressive Glomerulonephritis (RPGN) and subtypes of Focal Segmental Glomerulosclerosis (FSGS), in particular collapsing and cellular variants, are marked by initial podocyte injury and detachment, which triggers aberrant proliferation of neighboring parietal epithelial cell (PEC), resulting in crescent or pseudocrescent formation and eventual glomerulosclerosis. Previous studies suggest the crosstalk between podocytes and parietal epithelial cells (PECs) might play a role in the pathogenesis of these hyperplastic lesions, but the mechanisms remain unclear. Activation of Signal Transducer and Activator of Transcription 3 (STAT3) has been implicated in the initiation and progression of both RPGN and collapsing FSGS. Although activation of STAT3 signaling plays an important role in the pathogenesis of RPGN and subtypes of FSGS, the regulation of STAT3 signaling remains to be explored. Recent studies demonstrate that a zinc-finger transcription factor, Krüppel-Like Factor 4 (KLF4), might serve as a key negative regulator of STAT3 signaling. Although several members of the KLF family have been implicated in cell differentiation, KLF4 was first identified as a critical negative regulator of proliferation. Our preliminary data suggests that the podocyte-specific loss of Klf4 in mice renders the activation of dysregulated glomerular STAT3 signaling, podocyte injury, PEC proliferation, and eventual FSGS and renal failure. Furthermore, we showed that the activation of STAT3 signaling inversely correlated with KLF4 expression in the glomeruli of kidney biopsies with RPGN as compared to control specimens. Based on these data, we hypothesize that podocyte-specific KLF4 is required for the maintenance of podocyte integrity and prevention of aberrant PEC proliferation in proliferative glomerulopathies. We propose to test this hypothesis through the following specific aims: (1) Investigate the requisite role of podocyte-specific KLF4-STAT3 signaling in proliferative glomerulopathies and (2) Determine the central mechanisms mediating podocyte-PEC crosstalk in proliferative glomerulopathies. This research proposal aims to address a current gap in the field by elucidating the mechanisms by which podocyte loss triggers aberrant proliferation in the PECs in proliferative glomerulopathies. The long-term goal of our project is to identify dysregulated pathways inducing PEC proliferation that might serve as “druggable” targets in the development and/or progression of proliferative glomerulopathies.


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: 2024 ( Subtotal = $562,050 )
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/8/2024	NON-COMPETING CONTINUATION	$488,558
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	5/9/2024	SUPPLEMENT FOR EXPANSION	$73,492
														Subtotal = $562,050

Issue Date FY: 2023 ( Subtotal = $582,407 )
2023	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/18/2023	SUPPLEMENT FOR EXPANSION	$73,492
2023	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/12/2023	NON-COMPETING CONTINUATION	$508,915
														Subtotal = $582,407

Issue Date FY: 2022 ( Subtotal = $508,915 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/20/2022	NON-COMPETING CONTINUATION	$508,915
														Subtotal = $508,915

Issue Date FY: 2021 ( Subtotal = $513,063 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/17/2021	NON-COMPETING CONTINUATION	$513,063
														Subtotal = $513,063

Issue Date FY: 2020 ( Subtotal = $561,924 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/14/2020	NEW	$561,924
														Subtotal = $561,924

Grand Total All Awards = $2,728,359

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Mechanisms mediating podocyte-parietal epithelial cell crosstalk in proliferative glomerulopathies

Award Number: R01DK121846

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: 09/14/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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