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UNDERSTANDING THE ROLE OF TM2D FAMILY GENES IN NOTCH SIGNALING AND ALZHEIMER'S DISEASE

Award Number: R01AG071557
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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UNDERSTANDING THE ROLE OF TM2D FAMILY GENES IN NOTCH SIGNALING AND ALZHEIMER'S DISEASE - PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a multifactorial and complex neurodegenerative disorder that involves numerous genetic, epigenetic and environmental factors. Advances in genomics have identified new genes and rare variants that are associated with AD. However, the molecular mechanisms of how these factors contribute to AD pathogenesis are largely undefined. In collaboration with the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium, we recently identified a rare missense variant in TM2D3 that is associated with a significant increase in the risk of late-onset AD (LOAD). Furthermore, a recent study by an independent group reported that another rare missense variant was found in a patient with early-onset AD. Although the function of this gene has not been explored in vertebrates in vivo, our experiments using fruit flies, Drosophila melanogaster, suggests that this gene is a potential regulator of a key enzyme that process APP, a precursor protein that produces neurotoxic Ab42 peptides that contribute to AD. In this proposal, we elucidate the molecular function of TM2D3 and its related family members (TM2D1/2) to understand their role in APP processing and AD pathogenesis using Drosophila. Flies are excellent model organisms to genetically dissect molecular mechanisms of neurodegeneration. Moreover, since APP is processed by the same set of enzymes that activate Notch, a pathway affected in TM2D3 mutant flies, rich research infrastructure for Notch signaling studies in Drosophila greatly facilitates the mechanistic study of this protein in vivo. By combining genetic, cell biological, biochemical, electrophysiological and behavioral methodologies, we will uncover how TM2D3 and its relatives modulate proteolysis of membrane proteins to understand how rare missense variants in this gene affects the risk of LOAD and EOAD in humans. Such understanding will provide novel insights into AD pathogenesis and will deliver a new framework to understand how genetic risk factors of AD may impinge on a common molecular pathway to facilitate disease expression and progression.


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 = $394,475 )
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	3	4/8/2025	NON-COMPETING CONTINUATION	$360,001
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	002	3	5/29/2025	NON-COMPETING CONTINUATION	$1,125
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	003	3	6/13/2025	NON-COMPETING CONTINUATION	$32,099
2025	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	001	2	5/28/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,250
														Subtotal = $394,475

Issue Date FY: 2024 ( Subtotal = $400,000 )
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	2	4/22/2024	EXTENSION WITH OR WITHOUT FUNDS	$400,000
														Subtotal = $400,000

Grand Total All Awards = $794,475

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UNDERSTANDING THE ROLE OF TM2D FAMILY GENES IN NOTCH SIGNALING AND ALZHEIMER'S DISEASE

Award Number: R01AG071557

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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