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Microglial Hv1 Proton Channel as a Mediator of Environmentally-Induced Neuroinflammation and Neurodegeneration

Award Number: R01ES033892
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Neuroinflammation is a driving force contributing to neurodegenerative diseases, including Parkinson's disease (PD). Microglia are the primary immune cell of the brain and are among the first responders to infection, toxic insult and aggregated proteins and contribute significantly to neuroinflammation and neurodegeneration. The microglial inflammatory response, including inflammasome activation, has been demonstrated to be significantly associated with PD. Paraquat (PQ) is a commonly used herbicide that has been linked to increased risk for PD. PQ-induced neurodegeneration is tightly coupled to the activation of microglia and appears to require priming of the microglial response. Therefore, factors that modulate the microglial inflammatory response could lead to neuroprotection and slow the progression of neurodegenerative diseases. However, to date, no anti- inflammatory drugs have proven successful in human clinical trials necessitating research on new targets. Hv1 (HVCN1) is a voltage-gated proton channel highly expressed on microglia in the brain and in other immune cells in the body. This proton channel regulates the activity of NADPH oxidase and production of reactive oxygen species in immune cells and especially microglia. Our preliminary data demonstrate that PQ directly increases Hv1 levels in microglia, possibly through an epigenetic mechanism involving histone acetylation. Further, our data demonstrate effects of PQ on the NLRP3 inflammasome that appear to be regulated by Hv1, providing a potential mechanism contributing to PQ-induced microglial priming. This proposal seeks to test the hypothesis that Hv1 regulates priming of microglia following PQ exposure through the NLRP3 inflammasome, leading to neuroinflammation and neurodegeneration. The Specific Aims of this project are to 1) Determine mechanisms of Hv1 regulation following paraquat exposure 2) Define the role of Hv1 in regulation of the NLRP3 inflammasome following paraquat exposure and 3) Determine the contribution of microglial Hv1 and the NLRP3 inflammasome in regulating neurodegeneration following paraquat exposure. Completion of these Aims will define regulatory mechanisms for Hv1 and determine the role of Hv1 in regulation of the NLRP3 inflammasome activation and their role in PQ-induced neuroinflammation and neurotoxicity. Together, these Aims will provide crucial information on the function of a novel regulator of neuroinflammation, Hv1, and determine whether targeting Hv1 may be a viable therapeutic strategy in toxicant-induced neurodegeneration.


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: 2024 ( Subtotal = $625,498 )
2024	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Environmental Health	005	3	4/15/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$574,504
2024	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Environmental Health	001	3	2/14/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$625,498
2024	2023	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Environmental Health	004	2	4/15/2024	SUPPLEMENT FOR EXPANSION	-$220,240
2024	2023	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Environmental Health	000	2	2/13/2024	NON-COMPETING CONTINUATION	$0
2024	2023	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Environmental Health	002	2	2/15/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2023	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Environmental Health	003	2	4/15/2024	NON-COMPETING CONTINUATION	-$354,264
														Subtotal = $625,498

Issue Date FY: 2023 ( Subtotal = $961,899 )
2023	2023	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Environmental Health	000	2	1/4/2023	NON-COMPETING CONTINUATION	$593,149
2023	2023	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Environmental Health	001	2	3/24/2023	SUPPLEMENT FOR EXPANSION	$368,750
														Subtotal = $961,899

Issue Date FY: 2022 ( Subtotal = $605,024 )
2022	2022	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Environmental Health	000	1	3/4/2022	NEW	$605,024
														Subtotal = $605,024

Grand Total All Awards = $2,192,421

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Microglial Hv1 Proton Channel as a Mediator of Environmentally-Induced Neuroinflammation and Neurodegeneration

Award Number: R01ES033892

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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