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Manipulating DNA repair enzymes to examine the interactions between aging and Alzheimers disease with iPSC-derived microglia

Award Number: R01AG056303
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Microglia are strongly implicated in the pathogenesis of Alzheimer's disease (AD) and recent genetic studies have identified several microglial-enriched genes that influence AD risk. To study the role of these genes in AD our lab recently developed a fully-defined approach to differentiate induced pluripotent stem cells (iPSCs) into microglia. However, reprogramming erases many of the key signatures of aging, making it difficult to study the interactions between AD genes, pathology, and aging with iPSC-derived cells. One recent study developed an innovative approach to address this challenge by using Progerin, a protein associated with a premature aging disorder. However, the Progerin gene, LMNA, is not normally expressed in human neurons or glia. In contrast, another form of Progeria, Cockayne Syndrome (CS), which is caused by mutations that impair DNA repair, leads to significant neurological defects. Furthermore, two of the genes that are mutated in CS, ERCC1 and ERCC5, are highly expressed in human microglia and their deletion in mice mimics key aspects of microglial aging. Given these findings, we propose to test the hypothesis that deletion or mutations of ERCC1 and ERCC5 will produce changes in iPSC-derived microglia that mimic the effects of chronological aging and impair the response of microglia to AD-associated insults. To achieve these goals, we have assembled a multidisciplinary team who bring expertise in AD iPSC modeling, CRISPR-mediated gene deletion, and microglial differentiation and analysis, RNA-sequencing and bioinformatics, and brain organoid culture systems to test following three specific aims and hypotheses: Aim 1: Examine the impact of ERCC1/5 deletions and mutations on iPSC-derived microglial function. We hypothesize that ERCC knockout and mutant microglia will exhibit an age-associated `primed' activation state with impaired homestatic activity but exacerbated inflammatory responses. Aim 2: Do ERCC1/5 deletions and mutations model the transcriptional effects of aging observed in human brain-derived microglia? We hypothesize that deletion of these genes will produce microglia that exhibit many of the transcriptional changes associated with natural brain aging. Aim 3: Defining the intrinsic versus extrinsic effects of ERCC deletion on microglial aging with brain organoid cultures. We hypothesis that both intrinsic and extrinsic signals influence microglial aging.


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: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	000	5	10/12/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $386,250 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Aging Research	000	5	5/17/2021	NON-COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2020 ( Subtotal = $386,250 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Aging Research	000	4	4/30/2020	NON-COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2019 ( Subtotal = $386,250 )
2019	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Aging Research	000	3	5/1/2019	NON-COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2018 ( Subtotal = $386,250 )
2018	2018	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Aging Research	000	2	5/10/2018	NON-COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2017 ( Subtotal = $386,250 )
2017	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Aging Research	000	1	7/14/2017	NEW	$386,250
														Subtotal = $386,250

Grand Total All Awards = $1,931,250

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Manipulating DNA repair enzymes to examine the interactions between aging and Alzheimers disease with iPSC-derived microglia

Award Number: R01AG056303

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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