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Mechanisms and indicators of inflammasome signaling in Parkinson’s disease

Award Number: R01ES033462
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/21/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Mechanisms and indicators of inflammasome signaling in Parkinson’s disease - PROJECT SUMMARY The ViCTER Consortium has been established to characterize mechanisms of inflammation in the peripheral myeloid immune compartment, determine their impact on pesticide-driven neurodegeneration, and see if plasma- borne indicators of these processes are associated with military occupation and Parkinson’s disease (PD). It is widely accepted that complex gene-environment interactions underlie the risk of PD. Our work in pesticide- exposed mice and PD patients indicates that environmental toxicants converge on the NLRP3 inflammasome. Inflammasomes are intracellular multi-protein pattern recognition complexes that initiate and propagate inflammation in response to cellular damage and stress associated with the reversible process of pyroptotic cell death. The NLRP3 inflammasome has emerged as a key mediator of inflammation in PD, in part because it can sense non-microbial inflammatory triggers commonly associated with chronic, age-related neurodegenerative disorders. NLRP3 inflammasome triggers identified in models of PD include pesticides, heavy metals, mitochondrial and oxidative stress, and proteinaceous insult. Environmental toxicant exposure is often systemic and there is a growing appreciation of the role of the peripheral immune system in the response to toxicants and the progression of PD. Characterizing PD-related mechanisms in peripheral immune cells may help to identify signatures relevant to the progression of PD. Our studies in mice systemically exposed to rotenone identify a Nlrp3-dependent peripheral immune response co-occurring with nigral neurodegeneration. Our study of PD patients identified easily detectable plasma-borne indicators of NLRP3 inflammasome activity and elevated plasma NLRP3 protein in PD patients, potentially related to military employment. These data provide a compelling backdrop for our proposed characterization of peripheral NLRP3 activity in the context of PD. We have developed innovative mouse models based on CRE-driven cell-type specific Nlrp3 gain-of-function. We will limit Nlrp3 expression to peripheral myeloid cells and characterize the peripheral immune response, neuroinflammation, and nigral neurodegeneration using an established rotenone exposure-based PD model. In a second aim, we follow up on pilot studies to determine if the anti-inflammatory neuroprotective protein Regulator of G-protein Signaling 10 (RGS10) functions to resolve NLRP3-inflammasome signaling. In a third Aim, we team with the White River Junction VA Medical Center to evaluate subjects with prior military experience, using established assays to characterize the relationship between circulating inflammasome-related proteins, military occupation, and PD. Our ViCTER Consortium brings together experts in NLRP3 and toxicant-based models of PD, RGS10 and PD-related immunology, and patient-based studies. The collaborators will employ interdisciplinary strategies to characterize clinically relevant inflammatory mechanisms and inflammasome activity in an at-risk patient population. Studies will provide a foundation for the development of diagnostic tools and therapies to monitor, stratify, and treat PD.


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 = -$1,138 )
2026	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Environmental Health	000	3	1/28/2026	NON-COMPETING CONTINUATION	-$1,138
														Subtotal = -$1,138

Issue Date FY: 2023 ( Subtotal = $606,945 )
2023	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Environmental Health	000	3	8/14/2023	NON-COMPETING CONTINUATION	$606,945
														Subtotal = $606,945

Issue Date FY: 2022 ( Subtotal = $616,414 )
2022	2022	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Environmental Health	000	2	8/19/2022	NON-COMPETING CONTINUATION	$616,414
														Subtotal = $616,414

Issue Date FY: 2021 ( Subtotal = $673,223 )
2021	2021	TRUSTEES OF DARTMOUTH COLLEGE	6001 PARKHURST HALL STE 207	HANOVER	NH	03755	GRAFTON	USA	Environmental Health	000	1	9/21/2021	NEW	$673,223
														Subtotal = $673,223

Grand Total All Awards = $1,895,444

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Mechanisms and indicators of inflammasome signaling in Parkinson’s disease

Award Number: R01ES033462

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/21/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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