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Integrating Drosophila and human podocyte studies to discover APOL1 renal toxicity mechanism and therapeutic targets

Award Number: R01DK120908
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: 03/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Integrating Drosophila and human podocyte studies to discover APOL1 renal toxicity mechanism and therapeutic targets - African Americans face elevated risk of kidney disease, due in large part to inheritance of APOL1 risk alleles (RA). The molecular and cellular mechanisms underlying APOL1 nephropathy are being extensively investigated, but the mechanism remains unclear and potential therapeutic targets remain hidden. We generated a Drosophila model to study APOL1 nephropathy and showed that APOL1-RA led to renal cell injury in nephrocytes, the insect structural and functional homologs of human podocytes. The recently developed mouse APOL1 model provides a critical tool to study the molecular mechanism of APOL1 nephropathy and to test promising treatments, but it cannot be used to conduct large-scale genetic screens to identify modifier genes that could antagonize the renal toxicity of APOL1-RA. It is also extremely difficult to use the mouse model to screen for hundreds of candidate drug compounds. The Drosophila system presents unique advantages in terms of low-cost and high-efficiency, making it an ideal model for modifier genetic screening to identify novel APOL1-RA interacting factors that could rescue APOL1 renal toxicity, or to test hundreds of drug compunds identified from cell-based APOL1 drug screens. We propose the following three aims to exploit these unique advantages of Drosophila for APOL1 nephropathy studies: Aim 1, Identify downstream genes of APOL1-RA using RNA-Seq and cross-species comparison, and test them as potential therapeutic targets using Drosophila nephrocytes and human podocytes; Aim 2, Identify modifier genes for APOL1 renal toxicity using Drosophila genetic screening, and test them as potential therapeutic targets in nephrocytes and human podocytes; Aim 3, Use Drosophila as a drug screening platform to screen positive hits from a cell-based APOL1 drug screen. Accomplishing the above proposed aims will yield novel, ground-breaking discoveries to understand molecular mechanisms of APOL1 nephropathy. We will identify down-stream APOL1-RA target genes, identify potential therapeutic targets using Drosophila genetic screening plus human podocyte validation and screen the most effective and least toxic drug compounds that may eventually be used to treat APOL1 nephropathy.


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 = $0 )
2025	2022	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/21/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $347,625 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	3/25/2022	NON-COMPETING CONTINUATION	$34,761
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/16/2021	NON-COMPETING CONTINUATION	$312,864
														Subtotal = $347,625

Issue Date FY: 2021 ( Subtotal = $347,625 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	2/2/2021	NON-COMPETING CONTINUATION	$34,761
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/15/2020	NON-COMPETING CONTINUATION	$312,864
														Subtotal = $347,625

Issue Date FY: 2020 ( Subtotal = $347,625 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/2/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$347,625
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	2	5/29/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$358,781
2020	2019	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	5/29/2020	NEW	-$358,781
2020	2019	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/26/2020	NEW	$0
														Subtotal = $347,625

Issue Date FY: 2019 ( Subtotal = $401,625 )
2019	2019	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/19/2019	NEW	$401,625
														Subtotal = $401,625

Grand Total All Awards = $1,444,500

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Integrating Drosophila and human podocyte studies to discover APOL1 renal toxicity mechanism and therapeutic targets

Award Number: R01DK120908

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: 03/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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