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APOL1 Nephropathy: Linking Genetics and Mechanisms

Award Number: R01MD014726
ORGANIZATION: NATIONAL CENTER ON MINORITY HEALTH AND HEALTH DISPARITIES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/14/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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APOL1 Nephropathy: Linking Genetics and Mechanisms - SUMMARY African Americans develop kidney failure at rates 4-5 fold higher than European Americans. Coding variants in the APOL1 gene, found only in people of recent African ancestry, drive a large fraction of this risk disparity. We have named these APOL1 variants G1 (S342G and I384M) and G2 (del388N389Y). Risk inheritance is recessive: only individuals carrying two variant APOL1 alleles have a markedly increased risk of kidney disease. In the U.S. approximately 13% of African Americans, or about 4,000,000 people, have a high-risk genotype. Most recessive diseases are caused by loss-of- function mutation. Surprisingly, there is data from model systems in kidney cells, mice, drosophila, and yeast that support the idea that the APOL1 risk variants (RV) are actually gain-of-function mutations that cause toxicity when expressed at high levels. The overarching goal of this proposal is to understand the mechanism of APOL1 kidney disease such that two RVs are required, providing insight into this fundamental question of recessive, gain-of-function toxicity. We propose that the G0, or wild- type, APOL1 allele can alter the behavior of the risk variants and thus prevent their toxicity. In AIM 1, we will use isogenic, Crispr-engineered APOL1 BAC transgenic mice to determine the differing properties of G0 and risk-variant APOL1 in the full complexity of the glomerulus. We will test the effects of different APOL1 variants singly and in combination in order to answer questions about gene dosage, WT rescue of risk-variant toxicity, and possible differences in mechanism of action between the two major APOL1 risk alleles (G1 and G2). In AIM 2, our goal is to understand APOL1 targeting to lipid droplets. We have observed that lipid droplets (LDs) show prominent G0 but little or no G1 or G2 localization in cell systems and that co-expression of G0 facilitates the movement of G1 or G2 onto lipid droplets. We will use imaging and biochemical analyses to examine determinates of APOL1 localization to LDs, determine if there are differences in the binding of APOL1 to other LD-associated proteins, and define the cellular consequence(s) of altered APOL1 risk variant targeting to the LD. We will test the relevance of these experiments with in vivo studies. In AIM 3, we will determine the role of aggregation in APOL1-mediated cytotoxicity. We have observed that the APOL1 RVs have much stronger propensity than G0 to aggregate. Our data indicate that RV aggregation occurs in mitochondria. We hypothesize that aggregation is a key element in RV toxicity, and that G0 can interfere with RV aggregation. In cell-based systems we will characterize the APOL1 aggregates, determine whether aggregation is essential for APOL1-mediated cytotoxicity, understand the effect of aggregates on mitochondrial function, and test whether G0 can reverse RV aggregation and cytotoxicity. In vitro results will be validated in kidney organoids, a mouse model, and in human tissues.


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 = $463,893 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Minority Health and Health Disparities Research	001	5	5/24/2024	NON-COMPETING CONTINUATION	$33,477
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Minority Health and Health Disparities Research	000	5	12/5/2023	NON-COMPETING CONTINUATION	$430,416
														Subtotal = $463,893

Issue Date FY: 2023 ( Subtotal = $478,239 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Minority Health and Health Disparities Research	001	4	2/10/2023	NON-COMPETING CONTINUATION	$47,823
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Minority Health and Health Disparities Research	000	4	12/8/2022	NON-COMPETING CONTINUATION	$430,416
														Subtotal = $478,239

Issue Date FY: 2022 ( Subtotal = $478,239 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Minority Health and Health Disparities Research	001	3	4/28/2022	NON-COMPETING CONTINUATION	$47,823
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Minority Health and Health Disparities Research	000	3	12/10/2021	NON-COMPETING CONTINUATION	$430,416
														Subtotal = $478,239

Issue Date FY: 2021 ( Subtotal = $478,239 )
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Minority Health and Health Disparities Research	001	2	3/11/2021	NON-COMPETING CONTINUATION	$47,823
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Minority Health and Health Disparities Research	000	2	12/7/2020	NON-COMPETING CONTINUATION	$430,416
														Subtotal = $478,239

Issue Date FY: 2020 ( Subtotal = $478,239 )
2020	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Minority Health and Health Disparities Research	000	1	2/14/2020	NEW	$478,239
														Subtotal = $478,239

Grand Total All Awards = $2,376,849

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APOL1 Nephropathy: Linking Genetics and Mechanisms

Award Number: R01MD014726

ORGANIZATION: NATIONAL CENTER ON MINORITY HEALTH AND HEALTH DISPARITIES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/14/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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