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The role of the frontotemporal dementia gene product Progranulin (PGRN) in the homeostasis of the aging- and neurodegeneration-associated lipid Bis(monoacylglycero)phosphate

Award Number: K99AG097986
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/11/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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The role of the frontotemporal dementia gene product Progranulin (PGRN) in the homeostasis of the aging- and neurodegeneration-associated lipid Bis(monoacylglycero)phosphate - Project Summary Aging is the primary risk factor for Alzheimer’s disease-related dementias (ADRD) and frontotemporal dementia (FTD), with lysosomal dysfunction emerging as a central driver of pathology. Progranulin (PGRN), a lysosomal glycoprotein critical for neuronal health, regulates bis(monoacylglycero)phosphate (BMP)—a lipid essential for lysosomal function and neuronal survival. Reduced BMP levels in PGRN-deficient models correlate with neurodegeneration in FTD and neuronal ceroid lipofuscinosis. However, the molecular mechanisms coupling PGRN to BMP regulation remain unresolved, hindering BMP-based therapies to restore lysosomal health. This project addresses this gap by investigating PGRN’s interaction with PLA2G15, the BMP-degrading enzyme Dr. Xiong recently identified, and defining the roles of PGRN’s seven granulin domains. Leveraging unique mouse models (Grn, Pla2g15, Cln5 knockouts) and advanced mass spectrometry, Dr. Xiong will (Aim 1) test how PGRN-PLA2G15 binding governs BMP homeostasis, (Aim 2) map granulin-specific interactomes to unravel their lysosomal roles, and (Aim 3) evaluate BMP’s therapeutic potential with 5XFAD mice, a model of ADRD. Dr. Xiong developed a Career Development Plan tailored to accomplish this project to complement his expertise in lysosomal biology, genetics and metabolomics (as evident by 20 publications including 4 first-author studies since 2014). This work will be performed under co- mentorship from Dr. Monther Abu-Remaileh (lysosomal metabolism) and Dr. Tony Wyss-Corey (Aging and Alzheimer’s), alongside advisors Dr. Carolyn Bertozzi (Chemical biology), Dr. Anne Brunet (Aging and genetics), Dr. Michael Snyder (Genetics and system biology), Dr. Aaron Gitler (iPSC) and Dr. Yann Le Guen (Statistician), to ensures comprehensive training in translational therapeutic design and neurodegeneration models. In Aim 1, Dr. Xiong will train iPSC skills with Dr. Gitler and will use iPSC derived microglia as a cell model to test the function consequence of GRN deletion. In Aim 2, Dr. Xiong will train with Dr. Bertozzi to use acquire granulin interactome data and train with Dr. Snyder and Dr. Le Guen to learn how to analyze big data and generate hypothesis and insight in a system biology perspective in the K99 phase of this aim. In Aim 3, Dr. Xiong will train with Dr. Wyss-Corey and Dr. Brunet to learn designing longitudinal experiments to aging and Alzheimer mice to evaluate impact of BMP on age-related metabolism change and neuroinflammation and neurodegeneration. The K99 phase of this project will be conducted at Stanford University, which offers state- of-the-art facilities and a collaborative environment. Dr. Xiong will keep in touch with all the advisory committee after K99 phase. The K99/R00 award will enable the Dr. Xiong’s transition to independence, positioning him to lead high-impact research at the intersection of lysosomal biology and therapeutic development. By resolving PGRN’s role in BMP regulation and validating BMP elevation as a therapeutic strategy, this work addresses the NIA’s mission to combat age-related cognitive decline.


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 = $125,000 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	000	1	9/11/2026	NEW	$125,000
														Subtotal = $125,000

Grand Total All Awards = $125,000

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The role of the frontotemporal dementia gene product Progranulin (PGRN) in the homeostasis of the aging- and neurodegeneration-associated lipid Bis(monoacylglycero)phosphate

Award Number: K99AG097986

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/11/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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