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Toxicant-induced neurotoxicity mediated by glia-neuron and gene-environment interactions in Parkinson's disease

Award Number: R35ES030523
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary The long term goal of our laboratory is to study the pathogenic mechanisms induced by environmental toxicants, genetic mutations and gene-environment interactions in Parkinson’s disease (PD) with the ultimate goal of developing disease-modifying therapeutics for this brain disorder. Overall, our research projects address the following fundamental questions: 1) Gene- environment interactions: Do mutations linked to PD render dopamine neurons more susceptible to environmental toxicants? 2) Glia-neuron interactions: How do glial cells contribute to the vulnerability of dopamine neurons in PD? 3) Excessive mitochondrial fission has been demonstrated in genetic and toxicant-induced models of PD. Can mitochondrial fission and fusion be targeted for PD treatment? These research projects have been supported by NIEHS since 2006. This R35 proposal will be built upon the strength, expertise, experimental models and other resources generated from the NIEHS funded projects in our laboratory to take our work to the next transformative level. The primary goal of this R35 proposal is to demonstrate that neurotoxicity induced by neurotoxicants such as manganese (Mn) alone or in combination with other factors (α-synuclein and gastric bacteria) linked to PD can be mitigated by reducing the function of dynamin related protein-1 (Drp1), which is typically known as a mitochondrial fission protein. However, our recent findings have led us to unexpected and exciting mechanism of Drp1 through autophagy. Combined with our recent discoveries that neurotoxicants such as Mn and paraquat impair autophagy at a low and sub-lethal concentration, our vision is that Drp1 plays a central role in pathogenic mechanism and this protein can be targeted for PD therapy. Over the next eight years, this R35 will give us the flexibility and power to fully investigate the extensive involvement of Drp1 in neurotoxicity mediated by glia-neuron interactions, gene-environment interactions and gastric bacteria that have been linked to PD. This proposal utilizes a transdisciplinary approach from a team of accomplished investigators with relevant established track-records, a wide range of chemical and genetic tools, high standard techniques and innovative experimental models for molecular target manipulations with functional studies at cellular, circuit and whole animal levels. Completion of this project will provide paradigm shifts in our understanding of how Drp1 mediates neurotoxicity through a wide range of toxic insults.


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 = $0 )
2025	2024	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Environmental Health	000	6	10/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $860,151 )
2024	2024	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Environmental Health	000	6	5/7/2024	NON-COMPETING CONTINUATION	$860,151
														Subtotal = $860,151

Issue Date FY: 2023 ( Subtotal = $849,345 )
2023	2023	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Environmental Health	001	5	4/21/2023	NON-COMPETING CONTINUATION	$833,152
2023	2023	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Environmental Health	002	5	4/25/2023	SUPPLEMENT FOR EXPANSION	$16,193
2023	2022	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Environmental Health	000	4	4/6/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $849,345

Issue Date FY: 2022 ( Subtotal = $833,152 )
2022	2022	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Environmental Health	001	4	4/21/2022	NON-COMPETING CONTINUATION	$833,152
2022	2021	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Environmental Health	000	3	12/8/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $833,152

Issue Date FY: 2021 ( Subtotal = $833,153 )
2021	2021	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Environmental Health	000	3	4/23/2021	NON-COMPETING CONTINUATION	$833,153
														Subtotal = $833,153

Issue Date FY: 2020 ( Subtotal = $823,801 )
2020	2020	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Environmental Health	000	2	4/28/2020	NON-COMPETING CONTINUATION	$823,801
														Subtotal = $823,801

Issue Date FY: 2019 ( Subtotal = $788,577 )
2019	2019	FLORIDA INTERNATIONAL UNIVERSITY	11200 S W 8TH ST MARC 430	MIAMI	FL	33199	MIAMI-DADE	USA	Environmental Health	000	1	5/14/2019	NEW	$788,577
														Subtotal = $788,577

Grand Total All Awards = $4,988,179

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Toxicant-induced neurotoxicity mediated by glia-neuron and gene-environment interactions in Parkinson's disease

Award Number: R35ES030523

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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