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Evaluating the role of protein self-assembly in the innate immune system

Award Number: K00AG068511
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Evaluating the role of protein self-assembly in the innate immune system - As humans age, levels of proinflammatory cytokines increase, leading to a chronic inflammatory state, known as inflammaging. Inflammation is a hallmark of age-related diseases and increases mortality among the elderly. The molecular mechanisms that underlie inflammaging have not yet been elucidated. Therefore, there is an urgent need to elucidate the molecular mechanisms causing persistent proinflammatory signals, as doing so will accelerate efforts to prevent and treat age-related and autoinflammatory diseases. The overall goal of this proposal is to determine if a specific molecular mechanism contributes to the proinflammatory phenotype of aged monocytes. The data gathered so far reveals that multiple Death Domain proteins that function as key nodes downstream of pathogen recognition receptors are activated through a nucleation-limited assembly mechanism. The self-sustaining nature of this form of assembly should in principle allow them to persist indefinitely and continuously induce monocytes for proinflammatory signaling. The proposed aims will address two important questions: 1) Do protein self-assemblies suffice to establish and maintain a proinflammatory state in monocytes? 2) Are protein self-assemblies involved in the declining production and function of innate immune cells at the hematopoiesis level? In the F99-phase of this proposed research, the researcher aims to identify the molecular substrate that drives a persistent proinflammatory state in monocytes. The implementation of novel tools to measure functionality of protein self-assemblies in vivo, will address whether the assembled states of certain Death Domain proteins are functionally establishing a proinflammatory state in monocytes. In the K00-phase of this proposed research, the researcher will identify a potential mechanism of hematopoietic stem cell (HSC) decay and impaired self-renewal caused by signalosome formation. Specifically, the proposed experiments will determine whether Death Domain protein self-assemblies functionally reprogram HSC to skew the production of myeloid cells preloaded with a proinflammatory signature. To achieve these goals, the researcher will develop and implement novel approaches using cytological, biochemical and gene editing techniques. Completion of these aims will identify molecular substrates of inflammaging and reveal an unexplored role of ordered protein self-assemblies in signaling and cell differentiation. The proposed work is innovative and brings emerging biophysical concepts to the aging and immune senescence fields.


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 = $87,411 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	000	5	12/17/2024	NON-COMPETING CONTINUATION	$87,411
														Subtotal = $87,411

Issue Date FY: 2024 ( Subtotal = $82,891 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Aging Research	000	4	1/5/2024	NON-COMPETING CONTINUATION	$82,891
														Subtotal = $82,891

Issue Date FY: 2023 ( Subtotal = $79,992 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Aging Research	000	3	1/13/2023	EXTENSION WITH OR WITHOUT FUNDS	$79,992
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Aging Research	001	3	3/16/2023	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $79,992

Grand Total All Awards = $250,294

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Evaluating the role of protein self-assembly in the innate immune system

Award Number: K00AG068511

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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