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Interrogating the RIP kinase function of LRRK2 in chronic inflammation and susceptibility to infection.

Award Number: K22AI174008
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/02/2025
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Interrogating the RIP kinase function of LRRK2 in chronic inflammation and susceptibility to infection. - Project Summary Human genetic variants associated with mitochondrial dysfunction have been linked to chronic inflammatory diseases as well as susceptibility to infection. However, the mechanistic impact that these variants have on the immune system is poorly understood. I have discovered that macrophages harboring the common Parkinson’s disease associated variant, Lrrk2G2019S are more prone to cell death in response to both Mycobacterium tuber- culosis (Mtb) infection and AIM2 inflammasome activation. The enhanced cell death in Lrrk2G2019S macrophages is marked by mitochondrial stress and accumulated mitochondrial ROS. Interestingly Lrrk2G2019S cells are pushed from undergoing pyroptotic cell death to RIPK3/RIPK1/MLKL-mediated necroptosis. Consistent with elevated necroptotic cell death, infection of Lrrk2G2019S mice with Mtb elicits dramatic hyperinflammation and exacerbated pathogenesis via enhanced neutrophil infiltration. While these findings demonstrate that altered cellular homeo- stasis can reprogram canonical innate immune and cell death pathways to elicit distinct immune outcomes, the mechanistic contribution of the LRRK2-G2019S mutation on enhanced cell death remains a black box. Defining precisely how the Lrrk2G2019S variant promotes necroptotic cell death will help us to better understand why it is associated with susceptibility to chronic inflammatory and infectious diseases. Importantly, the Lrrk2G2019S variant has been shown to have enhanced RIP kinase activity. Additionally, previous studies have linked RIPK1 to LRRK2 as a potential substrate. I therefore propose that increased kinase activity conferred by the G2019S variant promotes a shift towards necroptotic cell death during pyroptosis by directly facilitating the activation of the RIPK1/RIPK3/MLKL signaling axis. To test this model, this proposal employs a cell biology (Aim 1) approach to identify kinase dependent interactions between LRRK2 and its substrates during pyroptosis and necroptosis, and an in vivo modeling (Aim 2) approach to observe which cell populations are undergoing necroptosis and identify the minimal requirements driving hyperinflammation. The goals of experiments de- scribed in this proposal will: 1.) uncover novel biology at the interface of cell death modalities, 2.) identify mech- anisms through which LRRK2 regulates and promotes cell death and inflammation, and 3.) map inflammatory phenotypes to connect in vitro biology with disease in vivo. The tools, training, and expertise described in this proposal will provide me with the experience necessary to establish a successful independent re- search program designed to interrogate how genetic mutations associated with mitochondrial dysfunction and chronic disease impact cell death programs in the immune system to drive pathogenesis.


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 = $108,000 )
2026	2026	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	000	2	5/7/2026	NON-COMPETING CONTINUATION	$108,000
														Subtotal = $108,000

Issue Date FY: 2025 ( Subtotal = $162,000 )
2025	2025	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	000	1	5/2/2025	NEW	$162,000
														Subtotal = $162,000

Grand Total All Awards = $270,000

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Interrogating the RIP kinase function of LRRK2 in chronic inflammation and susceptibility to infection.

Award Number: K22AI174008

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/02/2025

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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