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Mitochondrial defects in the retinal pigment epithelium and the CFH risk allele for age-related macular degeneration

Award Number: R01EY028554
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Mitochondrial defects in the retinal pigment epithelium and the CFH risk allele for age-related macular degeneration - Project Abstract/Summary Age-related macular degeneration (AMD) is the leading cause of blindness among older adults in the developed world. While recent studies support that mitochondrial (mt) defects in the retinal pigment epithelium (RPE) contribute to the pathogenesis of AMD, the causes of the dysfunction remains to be elucidated. Of the genetic polymorphisms linked to AMD, one of the most prevalent occurs in the gene encoding complement factor H (CFH). CFH is a negative regulator of the alternative complement pathway and protects against inappropriate complement activation that can cause chronic inflammation. The rs1061170 single-nucleotide polymorphism (SNP) in CFH, substituting a histidine at position 402 (Y402H) in the protein, is found in ~50% of AMD patients. How this single amino acid change contributes to AMD pathogenesis is unclear. Therefore, the goal of our proposed studies is to determine why the presence of the high risk CFH variant increases the prevalence of AMD disease. These studies build on our published work showing increased mtDNA damage in the RPE of AMD donors with the CFH high-risk SNP and a significant decrease in RPE mt function in induced pluripotent stem cell (iPSC)-RPE derived from donors harboring the high-risk allele. To accomplish our goal, we will use our collection of primary RPE and iPSC-derived RPE cultured from individuals phenotyped for AMD disease severity and genotyped for CFH risk. We will also use gene editing to create reciprocal isogenic iPSC-RPE lines from parent iPSCs containing either the CFH low or high risk allele. These model systems will be used to investigate how the presence of the CFH high risk allele alters RPE mt function and the response of RPE to metabolic and oxidative stressors. Aim 1 will test the hypothesis that intracellular complement regulates multiple cellular pathways that affect mt homeostasis and investigate how the presence of high risk 402H CFH variant protein alters these processes. Aim 2 will use a global metabolome and proteome approach to test the hypothesis that there are differences in metabolic and stress responsive pathways in RPE derived from donors with either the high or low risk CFH genotype. Findings from these studies will provide a comprehensive picture of the role of CFH in regulating RPE mt function by identifying cellular changes responsible for the loss in mt function and differences in stress response observed in RPE harboring the CFH high risk allele. This mechanistic insight could help explain the difference in AMD prevalence in CFH low versus high risk individuals. Knowledge about these differences may lead to development of therapies targeting the primary defect in a genetically defined population of AMD patients, which in turn, could lead to a “personalized medicine” approach for treatment of AMD.


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 = $619,785 )
2024	2024	DOHENY EYE INSTITUTE	150 N ORANGE GROVE BLVD	PASADENA	CA	91103	LOS ANGELES	USA	Vision Research	003	7	7/1/2024	NON-COMPETING CONTINUATION	$619,785
2024	2022	DOHENY EYE INSTITUTE	150 N ORANGE GROVE BLVD	PASADENA	CA	91103	LOS ANGELES	USA	Vision Research	002	5	1/3/2024	COMPETING CONTINUATION	$654
2024	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Vision Research	000	4	1/3/2024	NON-COMPETING CONTINUATION	-$501
2024	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Vision Research	001	3	1/3/2024	SUPPLEMENT FOR EXPANSION	-$153
														Subtotal = $619,785

Issue Date FY: 2023 ( Subtotal = $621,768 )
2023	2023	DOHENY EYE INSTITUTE	150 N ORANGE GROVE BLVD	PASADENA	CA	91103	LOS ANGELES	USA	Vision Research	000	6	6/23/2023	NON-COMPETING CONTINUATION	$621,768
														Subtotal = $621,768

Issue Date FY: 2022 ( Subtotal = $666,841 )
2022	2022	DOHENY EYE INSTITUTE	150 N ORANGE GROVE BLVD	PASADENA	CA	91103	LOS ANGELES	USA	Vision Research	001	5	9/20/2022	COMPETING CONTINUATION	$666,841
2022	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Vision Research	000	4	9/20/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $666,841

Issue Date FY: 2021 ( Subtotal = $567,508 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Vision Research	000	4	4/1/2021	NON-COMPETING CONTINUATION	$434,899
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Vision Research	001	3	9/15/2021	SUPPLEMENT FOR EXPANSION	$132,609
														Subtotal = $567,508

Issue Date FY: 2020 ( Subtotal = $452,969 )
2020	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Vision Research	000	3	4/16/2020	NON-COMPETING CONTINUATION	$452,969
														Subtotal = $452,969

Issue Date FY: 2019 ( Subtotal = $452,969 )
2019	2019	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Vision Research	000	2	3/14/2019	NON-COMPETING CONTINUATION	$452,969
														Subtotal = $452,969

Issue Date FY: 2018 ( Subtotal = $452,234 )
2018	2018	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Vision Research	000	1	3/15/2018	NEW	$452,234
														Subtotal = $452,234

Grand Total All Awards = $3,834,074

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Mitochondrial defects in the retinal pigment epithelium and the CFH risk allele for age-related macular degeneration

Award Number: R01EY028554

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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