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Mechanistic Investigation of Innate Immunity in a Drosophila Model of Frontotemporal Dementia

Award Number: R21AG085108
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Mechanistic Investigation of Innate Immunity in a Drosophila Model of Frontotemporal Dementia - Frontotemporal dementia (FTD) is the second most common presenile dementia after Alzheimer’s disease and shares many pathological and genetic overlaps with ALS. The most common genetic cause of FTD and ALS is a GGGGCC hexanucleotide repeat expansion in the first intron of the C9ORF72 gene. Although RNA toxicity and C9ORF72 haploinsufficiency may also contribute to disease pathogenesis in C9ORF72-related FTD/ALS, much efforts has focused on investigating the toxicity of dipeptide repeat (DPR) proteins that can be translated from both sense and antisense repeat RNAs. How these DPR proteins, especially poly(GR), cause neurodegeneration at the molecular mechanistic level remains largely unknown. In this exploratory R21 grant application, based on our recent findings that several antimicrobial peptide genes, such as metchnikowin (Mtk), are upregulated with poly(GR) toxicity in Drosophila and that Mtk knockdown in the eye or in all neurons suppresses poly(GR) neurotoxicity, we propose to further investigate this understudied pathway in neurodegeneration. In particular, we will investigate the molecular mechanisms underlying the effects of Mtk on poly(GR) toxicity, explore the non-cell autonomous neurodegenerative activity of Mtk, and finally attempt to identify mammalian AMP(s) that may function in a similar fashion as Drosophila Mtk in the molecular pathogenesis of FTD/ALS. These studiers will shed new light on pathogenic mechanisms of FTD/ALS and may help identify novel therapeutic targets for these disorders.


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 = $0 )
2026	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	000	1	7/7/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $460,625 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	000	1	4/3/2024	NEW	$460,625
														Subtotal = $460,625

Grand Total All Awards = $460,625

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Mechanistic Investigation of Innate Immunity in a Drosophila Model of Frontotemporal Dementia

Award Number: R21AG085108

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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