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Role of Rab10 in Alzheimer's disease

Award Number: R00AG075179
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Role of Rab10 in Alzheimer's disease - 1 Project Summary: “Role of Rab10 in Alzheimer’s disease, K99/R00” 2 Candidate: My long-term career goals center on the establishment of a leading research laboratory in 3 academia focused on defining key molecular mechanisms underlying neurodegeneration and Alzheimer’s 4 disease (AD). Specifically, my recent research interests have narrowed to ask how key regulators of endocytic 5 trafficking pathways, particularly Rab GTPases and their modifiers, contribute to neuroinflammation associated 6 with AD. I am a biochemist with training in biophysics and cell biology, with the included proposal for additional 7 training in mouse models of disease. These training experiences will facilitate future investigations in molecular 8 mechanisms underlying endocytic dysfunction that manifest in disease relevant phenotypes. 9 Training: Here I propose a series of training that include a translational in vivo experiment in mouse models 10 coupled with formal coursework to accelerate my trajectory towards independence in the R00 phase. These 11 training experiences will be facilitated through mentorship from Dr. Andrew West, in addition to a Transition 12 Advisory committee at Duke University composed of Dr. Patrick Sullivan, an expert in mouse AD models, Dr. 13 Carol Colton, an expert in microglia function in AD models, and Dr. Robert Lefkowitz, a Nobel-laureate expert 14 in biochemistry and cell biology. Formal course work that is planned will further enhance training on in vivo 15 study approaches, grant writing, mentoring skills, lab management and responsible conduct in research. 16 Research: Recently, a single nucleotide polymorphism in the Rab10 3’UTR rs142787485 has been linked with 17 strong resiliency to AD susceptibility. Transcriptomic analysis reveals Rab10 mRNA as higher in AD patient 18 brains compared to healthy controls. My latest post-doctoral work disclosed that the Rab10 GTPase, highly 19 expressed in phagocytic cells, operates in a specific compartment of the endolysosomal pathway to control 20 fluid phase macropinocytosis. Preliminary data included herein suggests knockdown of Rab10 decreases the 21 internalization of aggregated tau in mouse primary microglia. Recent findings suggest internalized tau 22 aggregates break endolysosomes in microglia that stimulate inflammasome activation and the secretion of 23 damaging cytokines. Inflammasome activation may accelerate tau pathology, potentially linking Rab10 with 24 neuroinflammatory pathways important in AD. I plan to explore this novel disease-associated cycle in K99 and 25 R00 work. In the K99 phase, I would test the hypothesis that suppression of Rab10 in the P301S Tau/APOE4 26 mouse model ameliorates neuroinflammation and neuropathology. In the R00 phase, I plan to investigate how 27 Rab10 might regulate aggregated tau uptake, processing, and responses in microglia, as well as key 28 regulators of Rab10 activity that influence different endocytic trafficking pathways and immunological 29 responses. These proposed experiments would start to elucidate the potential roles of Rab10 in AD, and 30 identify novel pathways that might be exploited in the future for therapeutic gain. 31 32 33


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 = $248,999 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	5	1/30/2026	NON-COMPETING CONTINUATION	$224,099
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	001	5	2/25/2026	NON-COMPETING CONTINUATION	$24,900
														Subtotal = $248,999

Issue Date FY: 2025 ( Subtotal = $244,019 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	4	11/25/2024	NON-COMPETING CONTINUATION	$224,099
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	001	4	8/4/2025	NON-COMPETING CONTINUATION	$19,920
														Subtotal = $244,019

Issue Date FY: 2024 ( Subtotal = $264,056 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	001	3	5/14/2024	EXTENSION WITH OR WITHOUT FUNDS	$15,056
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	3	5/14/2024	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $264,056

Grand Total All Awards = $757,074

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Role of Rab10 in Alzheimer's disease

Award Number: R00AG075179

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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