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Role of Retrotransposon Activity in Neurodegeneration and Alzheimer's Disease

Award Number: P01AG051449
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2016
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Role of Retrotransposon Activity in Neurodegeneration and Alzheimer's Disease - PROJECT SUMMARY (OVERALL) Retrotransposable elements (RTEs) comprise ~45% of the human genome. Known as ‘mobile DNA’ they can insert into new genomic locations using a 'copy and paste' mechanism. This process, retrotransposition, can be deleterious at multiple levels, and has largely been viewed as molecular parasitism. Not surprisingly, host organ- isms have evolved multiple silencing mechanisms to protect their genomes. This competitive and adversarial relationship between RTEs and their hosts is evident in the evolutionary record of genome sequences. This record is silent on the activity of RTEs in somatic tissues, since this information is not passed from one generation to another, and RTEs were thought to be largely silent in somatic cells. However, in the past 10-15 years evi- dence started emerging that somatic RTE activity is more frequent than anticipated, with members of this PPG contributing important early evidence. Five years ago, this debate culminated in the submission of this PPG, founded on the hypothesis that the somatic activation of RTEs represents a novel and hitherto unappreciated molecular aging process. Our research program was designed to test this hypothesis and elucidate the underly- ing mechanisms. The next five years saw a validation of this hypothesis, not just by our team, but also many other groups. It is now apparent that with aging, multiple host defense mechanisms become compromised, and repetitive sequences in general, not just active RTEs, increase their expression. As to the underlying mecha- nisms by which this somatic onslaught 'can hurt us' we were in for a surprise: we discovered that RTEs dere- pressed during aging, in particular LINE-1 (L1) elements, can generate cytoplasmically localized cDNA reverse transcripts. These cDNAs are potent activators of a Type-I Interferon (IFN-I) response, which in turn stimulates the innate immune system. We believe this leads to a phenomenon known as 'sterile inflammation' or 'inflam- maging', a known hallmark of aging that has been implicated in a variety of age-related diseases. In a nutshell, the host organism perceives RTE activation as an invading virus and mounts an appropriate anti-viral response – unfortunately, given that the invader is embedded in our genomes, this response is futile and ultimately coun- terproductive. Interestingly, the central nervous system (CNS) appears to be a 'privileged site' for RTE activity, with relatively high levels of expression and ease of further upregulation. Multiple lines of evidence indicate that RTE activation is associated with pathology, and in particular neuroinflammation. Neurodegenerative diseases, and in particular dementias such as Alzheimer's Disease (AD), are among the most devastating and feared diseases of aging. The goal of this PPG will be to explore in detail the newly discovered somatic L1 lifecycles in neuronal and non-neuronal cells of the CNS, the L1 surveillance mechanisms in the CNS, how they fail, the consequences of that failure, and ultimately, how we can fix this. We will use human induced pluripotent stem cell (iPSC) models as well as directly reprogrammed neurons, Drosophila and mouse models of AD, and human postmortem tissue. F.H. Gage, a widely-known AD pioneer, joins the original PPG team on this quest.


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: 2026 ( Subtotal = $3,197,786 )
2026	2026	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	000	10	1/9/2026	NON-COMPETING CONTINUATION	$2,878,009
2026	2026	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	001	10	2/23/2026	NON-COMPETING CONTINUATION	$319,777
														Subtotal = $3,197,786

Issue Date FY: 2025 ( Subtotal = $3,148,529 )
2025	2025	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	002	9	9/23/2025	NON-COMPETING CONTINUATION	$257,022
2025	2025	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	001	9	12/6/2024	NON-COMPETING CONTINUATION	$2,891,507
2025	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	000	8	10/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $3,148,529

Issue Date FY: 2024 ( Subtotal = $3,226,541 )
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	001	8	6/4/2024	NON-COMPETING CONTINUATION	$322,653
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	000	8	12/15/2023	NON-COMPETING CONTINUATION	$2,903,888
														Subtotal = $3,226,541

Issue Date FY: 2023 ( Subtotal = $3,239,922 )
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	000	7	1/4/2023	NON-COMPETING CONTINUATION	$3,239,892
2023	2020	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	001	5	5/11/2023	NON-COMPETING CONTINUATION	$30
														Subtotal = $3,239,922

Issue Date FY: 2022 ( Subtotal = $3,310,151 )
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	004	6	6/3/2022	COMPETING CONTINUATION	$261,873
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	002	6	3/1/2022	COMPETING CONTINUATION	$3,310,151
2022	2020	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	000	5	2/21/2022	NON-COMPETING CONTINUATION	$0
2022	2020	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	001	5	2/21/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2020	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	003	5	6/3/2022	SUPPLEMENT FOR EXPANSION	-$261,873
														Subtotal = $3,310,151

Issue Date FY: 2020 ( Subtotal = $2,282,873 )
2020	2020	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	000	5	5/26/2020	NON-COMPETING CONTINUATION	$1,886,623
2020	2020	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	001	5	7/17/2020	SUPPLEMENT FOR EXPANSION	$396,250
														Subtotal = $2,282,873

Issue Date FY: 2019 ( Subtotal = $2,294,890 )
2019	2019	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	000	4	6/17/2019	NON-COMPETING CONTINUATION	$1,888,640
2019	2019	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	001	4	6/19/2019	SUPPLEMENT FOR EXPANSION	$406,250
														Subtotal = $2,294,890

Issue Date FY: 2018 ( Subtotal = $2,359,658 )
2018	2018	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	000	3	8/3/2018	NON-COMPETING CONTINUATION	$1,914,535
2018	2018	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	001	3	9/13/2018	SUPPLEMENT FOR EXPANSION	$445,123
														Subtotal = $2,359,658

Issue Date FY: 2017 ( Subtotal = $2,127,604 )
2017	2017	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	001	2	8/21/2017	SUPPLEMENT FOR EXPANSION	$173,875
2017	2017	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	000	2	6/23/2017	NON-COMPETING CONTINUATION	$1,953,729
														Subtotal = $2,127,604

Issue Date FY: 2016 ( Subtotal = $2,028,370 )
2016	2016	BROWN UNIVERSITY	POST OFFICE BOX 1929	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	000	1	8/18/2016	NEW	$2,028,370
														Subtotal = $2,028,370

Grand Total All Awards = $27,216,324

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Role of Retrotransposon Activity in Neurodegeneration and Alzheimer's Disease

Award Number: P01AG051449

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2016

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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