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Cytosolic SINE retrotransposable element cDNA and mitochondrial DNA in aging retina

Award Number: R01AG082748
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Cytosolic SINE retrotransposable element cDNA and mitochondrial DNA in aging retina - PROJECT SUMMARY The retinal pigmented epithelium (RPE) is an amitotic, long-lived cell type that supports healthy visual function for numerous decades. The aging retina displays pathologic features that are exaggerated in a complex disease called age-related macular degeneration (AMD). Progressive degeneration of the aging RPE is a hallmark of geographic atrophy, a late-stage of AMD that causes vision loss. We recently discovered an excess abundance of cytosolic complementary DNA derived from the SINE retrotransposon element (RTE) Alu family in the RPE of human eyes with geographic atrophy and that cytosolic Alu cDNAs are highly cytotoxic to the RPE in animal and human cell-based studies. These Alu cDNAs are produced via reverse transcription of Alu RNAs by the long- interspersed nuclear element-1 (L1). We also found that Alu cDNAs trigger the cytosolic escape of mitochondrial DNA (mtDNA), and together these two cytosolic DNAs collaborate, in mechanistically unclear ways, to activate a multifaceted innate immune response that results in cell death. To gain a better understanding of the combinatory impact of Alu cDNAs and mtDNA and their causal contribution to aging in the retina, we will (1) create temporal, spatial, and sequence topographic maps of Alu cDNA subfamilies and mtDNA in young, healthy aged, and AMD-affected human eyes; (2) probe the stimuli for and mechanisms of Alu cDNA generation in aging by investigating whether L1 regulators influence Alu cDNA production and retinal toxicity; and (3) elucidate the pathway of mitochondrial dysfunction triggered by Alu cDNA and the noncanonical inflammatory pathways triggered by Alu cDNA and mtDNA joint activity that are responsible for retinal cell death. This proposal is responsive to RFA-AG-23-015 as it will provide mechanistic insights into how cytosolic Alu cDNAs and mtDNA mediate interactions of aging hallmarks and modulate healthspan by mapping their sequence and expression during aging, determining the regulation of their biogenesis, and delineating how they conspire with each other to promote cellular dysfunction in aging. Completion of these studies will reveal previously unexplored pathways with therapeutic relevance for developing transformative therapies to improve visual healthspan and potentially cognitive healthspan, as conditions such as Alzheimer’s disease share epidemiological and mechanistic features with 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: 2025 ( Subtotal = $614,163 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Aging Research	001	3	6/18/2025	NON-COMPETING CONTINUATION	$50,136
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Aging Research	000	3	3/24/2025	NON-COMPETING CONTINUATION	$564,027
														Subtotal = $614,163

Issue Date FY: 2024 ( Subtotal = $631,751 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Aging Research	000	2	4/18/2024	NON-COMPETING CONTINUATION	$631,751
														Subtotal = $631,751

Issue Date FY: 2023 ( Subtotal = $626,696 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Aging Research	000	1	8/15/2023	NEW	$626,696
														Subtotal = $626,696

Grand Total All Awards = $1,872,610

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Cytosolic SINE retrotransposable element cDNA and mitochondrial DNA in aging retina

Award Number: R01AG082748

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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