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Elucidating the role of CHI3L1/YKL-40 in Alzheimer’s disease

Award Number: R01AG083943
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Elucidating the role of CHI3L1/YKL-40 in Alzheimer’s disease - PROJECT SUMMARY/ABSTRACT Chitinase-3-like protein 1 (CHI3L1/YKL-40) is a well-known biomarker for the early detection of neuroinflammation and Alzheimer’s disease (AD). It acts as a master regulator of immunity in peripheral tissues, engaging defined cell surface receptors to regulate a wide range of injury and repair responses. In the brain, CHI3L1 is primarily secreted by astrocytes and indicates the reactive, neurotoxic state triggered by inflammation and other stress. The association with CHI3L1 expression and AD pathological and clinical manifestations is well established, but the exact mechanism by which CHI3L1 contributes to AD pathogenesis is still unclear. The dynamic interactions between microglia, astrocytes and neurons are central in the inflammatory neurotoxicity that leads to neurodegeneration in AD. Understanding the intricate cellular cross-talk in human neural systems, as well as the role of CHI3L1 in this process, thus signifies a critical need for developing therapeutics for AD. Using human stem cell-based methods and original transgenic mouse models, the overall objectives are twofold: i) to define the signaling mechanism whereby CHI3L1 governs neurodegeneration caused by glial activation; and ii) to develop the translational potential of these signaling mechanisms to prevent neuronal damage in AD. Our central hypothesis posits that CHI3L1, derived from astrocytes, functions as a signaling molecule that mediates inflammatory responses in a manner specific to different cell types, ultimately promoting neuronal degeneration and regulating microglial inflammatory profiles. Importantly, we also hypothesize that by silencing CHI3L1 signaling in neurons, we can mitigate neurotoxicity and ameliorate AD pathology. To dissect the complex interactions between brain cell types, we plan to utilize to iPSC-based cultures consisting of pure and mixed populations of human microglia, astrocytes and neurons. Furthermore, we will leverage our unique transgenic mouse strains with astrocyte-specific CHI3L1 conditional knockout to rigorously test our hypothesis. To accomplish the overall objectives, we will pursue the two specific aims: Aim 1 is to investigate how CHI3L1 induces neuronal apoptosis and neurodegenerative changes through interactions with receptors on neurons and microglia, by using iPSC-based neural culture systems to dissect the neuroprotective role of CHI3L1 and inspire the development of anti-neuroinflammatory therapeutics; Aim 2 is to determine the translational potential of targeting CHI3L1 signaling for neurodegeneration in AD, by manipulating astroglial expression of CHI3L1 and its identified neuronal receptor to remedy brain pathology and behavioral defects in AD-relevant mouse models. The expected outcomes of this study include defining a CHI3L1-mediated signaling mechanism that governs neurodegeneration in AD pathogenesis. This work is highly significant and innovative as it aims to elucidate the biological role of CHI3L1, a prominent AD biomarker. By understanding the involved molecular and cellular functions of CHI3L1, this study could pave the way for new treatments for AD and relevant 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 = $384,365 )
2026	2026	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	000	3	5/19/2026	NON-COMPETING CONTINUATION	$384,365
														Subtotal = $384,365

Issue Date FY: 2025 ( Subtotal = $377,285 )
2025	2025	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	000	2	7/3/2025	NON-COMPETING CONTINUATION	$377,285
														Subtotal = $377,285

Issue Date FY: 2024 ( Subtotal = $385,577 )
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	000	1	7/23/2024	NEW	$385,577
														Subtotal = $385,577

Grand Total All Awards = $1,147,227

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Elucidating the role of CHI3L1/YKL-40 in Alzheimer’s disease

Award Number: R01AG083943

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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