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Lysosome dysfunction in podocytopathy and associated hypertension

Award Number: R01DK120491
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: 09/25/2018
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Lysosome dysfunction in podocytopathy and associated hypertension - Project Summary Podocytopathy is an important pathogenic basis for different glomerular diseases such as minimal change disease (MCD), diffuse mesangial sclerosis, focal segmental glomerulosclerosis, collapsing glomeru- lonephropathy and global glomerulosclerosis associated with hyperhomocysteinemia (hHcy), obesity and diabetes mellitus. These glomerular diseases have been reported to account for the vast majority of end-stage renal disease and kidney-associated hypertension and cardiovascular diseases. Recent studies have indicated that normal autophagy is a critical cellular process to control podocyte function and even its life span and that deficient autophagy and associated autophagosome (AP) accumulation or increases in exosome release produce podocyte injury and podocytopathy. We have shown that a sphingolipid-mediated signaling pathway is importantly implicated in lysosome dysfunction, autophagic flux deficiency and ultimate podocytopathy and glomerular sclerosis. The present grant proposal will test a central hypothesis that lysosomal acid ceramidase (AC)-mediated sphingolipid metabolism critically controls lysosome trafficking or fusion to APs or multivesicular body (MVB) and subsequent degradation process determining the normal phenotype and function of podocytes. AC gene defect or functional deficiency may disturb lysosome degradation of APs and MVBs, which induces AP accumulation and exosome release from MVBs leading to podocyte phenotypic transition, effacement and ultimate MCD. To test this hypothesis, three Specific Aims are proposed. Specific Aim 1 will determine whether autophagic flux and exosome excretion in podocytes are fine controlled by lysosomal AC activity and whether the deficiency of this AC regulation causes podocytopathy and MCD in Asah1fl/fl/Podocre mice, but not in their littermates. Specific Aim 2 attempts to elucidate the central role of lysosomal AC- mediated sphingolipid signaling in the regulation of lysosome trafficking to and fusion with APs and MVBs for their degradation using podocyte-specific Asah1 gene deletion, rescuing and silencing. In Specific Aim 3, we will explore the mechanisms by which lysosome trafficking or fusion in podocytes is regulated by AC- associated sphingolipids via gating lysosomal TRPML1 channels and associated Ca2+ release using patch clamping of isolated lysosomes and lysosome-specific Ca2+ imaging with GCaMP3-ML as an indicator. These proposed studies will present a novel mouse model for podocytopathy and MCD and use this model to explore associated molecular mechanisms triggering podocytopathy. The grant proposal represents the first effort in the research field to investigate the AC-mediated lysosome regulation of autophagic flux and exosome excretion in podocytes and associated pathogenic role in potocytopathy. The findings may make paradigm shift in understanding pathogenesis of podocytopathy and MCD and help identify lysosomal AC as a therapeutic target for prevention or treatment of MCD and other glomerular diseases.


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: 2025 ( Subtotal = -$28,910 )
2025	2022	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/29/2025	NON-COMPETING CONTINUATION	-$28,910
														Subtotal = -$28,910

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	10/16/2023	NON-COMPETING CONTINUATION	$0
2024	2022	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	8/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $488,899 )
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	8/11/2022	NON-COMPETING CONTINUATION	$488,899
														Subtotal = $488,899

Issue Date FY: 2021 ( Subtotal = $488,899 )
2021	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/3/2021	NON-COMPETING CONTINUATION	$488,899
														Subtotal = $488,899

Issue Date FY: 2020 ( Subtotal = $488,899 )
2020	2020	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/16/2020	NON-COMPETING CONTINUATION	$488,899
														Subtotal = $488,899

Issue Date FY: 2019 ( Subtotal = $488,899 )
2019	2019	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/29/2019	NON-COMPETING CONTINUATION	$488,899
														Subtotal = $488,899

Issue Date FY: 2018 ( Subtotal = $488,243 )
2018	2018	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/25/2018	NEW	$488,243
														Subtotal = $488,243

Grand Total All Awards = $2,414,929

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Lysosome dysfunction in podocytopathy and associated hypertension

Award Number: R01DK120491

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: 09/25/2018

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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