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Altered reverse transcriptase-dependent gene diversification mechanisms in Alzheimer's disease brains

Award Number: R01AG065541
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Altered reverse transcriptase-dependent gene diversification mechanisms in Alzheimer's disease brains - PROJECT SUMMARY/ABSTRACT We have identified somatic gene recombination (SGR) in neurons of the human brain, with particular relevance to sporadic Alzheimer’s disease (SAD) (Nature 563, 639-645 (2018)). This discovery represents a new and functionally significant aspect of genomic mosaicism (eLife;4:e05116 (2015)) that has genuine therapeutic potential through newly identified molecular targets. Indeed, we found that SGR, acting on the AD gene for Amyloid Precursor Protein (APP), produces thousands of distinct forms of APP, some of which are enriched in or unique to AD. The APP gene variations related to AD that were analyzed thus far include copy number variations (CNVs) and at least 11 single-nucleotide variations (SNVs) that were previously reported as pathogenic in familial AD, yet that arose somatically and mosaically in SAD; these variations were absent from non-diseased neurons. SGR utilizes reverse transcriptase (RT) activity on transcribed RNAs that, combined with DNA strand-breaks and APP gene transcription, produce double-stranded DNA that is retro-inserted back into the genome to form “genomic cDNAs” (gencDNAs). These published data contribute to the scientific foundation on which the current proposal will build, to test the hypothesis that altered SGR, involving brain- specific reverse transcriptases, functionally contributes to AD and affects multiple genes, providing novel targets for AD therapies. Postmortem IRB-approved and de-identified brain samples from validated AD donors of both sexes will be compared to non-diseased controls, while IACUC-approved animal experiments will model SGR and its AD-relevant endpoints. Three Aims will be pursued over 5 years. Aim 1 will define the molecular neurobiology of APP gencDNA diversity and identify new SGR genes enhanced in AD brains. Aim 2 will determine expression and function of SGR genes in AD brain and model systems. Aim 3 will identify genes responsible for RT SGR activity within normal and AD brains. This proposal will thus open new vistas into AD via novel SGR mechanisms and will identify new therapeutic targets for the treatment of AD.


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 = $929,705 )
2024	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	5	1/4/2024	NON-COMPETING CONTINUATION	$836,735
2024	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	5	6/10/2024	NON-COMPETING CONTINUATION	$92,970
														Subtotal = $929,705

Issue Date FY: 2023 ( Subtotal = $1,013,514 )
2023	2023	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	4	1/26/2023	NON-COMPETING CONTINUATION	$929,705
2023	2023	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	4	1/27/2023	SUPPLEMENT FOR EXPANSION	$83,809
														Subtotal = $1,013,514

Issue Date FY: 2022 ( Subtotal = $1,047,035 )
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	11/26/2021	SUPPLEMENT FOR EXPANSION	$16,760
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	3	1/13/2022	NON-COMPETING CONTINUATION	$836,735
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	003	3	5/10/2022	NON-COMPETING CONTINUATION	$92,970
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	002	3	1/14/2022	SUPPLEMENT FOR EXPANSION	$100,570
														Subtotal = $1,047,035

Issue Date FY: 2021 ( Subtotal = $929,705 )
2021	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	1/28/2021	NON-COMPETING CONTINUATION	$929,705
														Subtotal = $929,705

Issue Date FY: 2020 ( Subtotal = $929,705 )
2020	2020	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	3/19/2020	NEW	$929,705
														Subtotal = $929,705

Grand Total All Awards = $4,849,664

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Altered reverse transcriptase-dependent gene diversification mechanisms in Alzheimer's disease brains

Award Number: R01AG065541

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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