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Mechanisms associated with neuroprotection from Mn-induced neurotoxicity.

Award Number: R01ES031282
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: 08/10/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Mechanisms associated with neuroprotection from Mn-induced neurotoxicity. - Project Summary Chronic exposure to high levels of manganese (Mn) causes manganism, a neurological disorder which shares multiple pathological features with Parkinson's disease (PD). Mn-induced neurotoxicity includes decreased expression of tyrosine hydroxylase (TH), a rate-limiting enzyme in dopamine synthesis, and dopaminergic neuronal injury. But the mechanisms of the Mn-induced neurotoxicity are not completely understood. Estrogenic compounds, such as tamoxifen, a selective estrogen receptor modulator (SERM), have been shown to be protective in Mn toxicity and PD, but their mode of action remains to be established. While the transcription factor RE1- silencing transcription factor (REST) was initially described as a repressor of neuronal genes in non-neuronal cells during development, it has recently been shown to play a critical role in protection of adult neurons, and it activates genes that are involved in neuroprotection. Our preliminary data reveal that Mn decreased REST, whereas TX increased its expression in TH- expressing neuronal cells. REST protected dopaminergic neurons against Mn neurotoxicity by attenuating Mn-induced oxidative stress, inflammation and apoptosis. These findings indicate that REST may mediate TX-induced neuroprotection against Mn toxicity in dopaminergic neurons. Therefore, investigating the mechanisms of REST in Mn-induced neurotoxicity and TX-induced protection against Mn toxicity is critical to advance our understanding of Mn neurotoxicity and in developing therapeutic strategies to treat neurodegenerative diseases associated with dysfunction of dopaminergic neurons. We hypothesize that REST protects against Mn neurotoxicity by enhancing expression of TH, as well as the antioxidant/antiapoptotic genes catalase (CAT) and B-cell lymphoma 2 (Bcl-2), and mediates TX-induced protection against Mn toxicity via genomic ERα and nongenomic ERα/GPR30 pathways. Our hypothesis will be tested in the following specific aims: 1) Test if REST in DAergic neurons is protective against Mn neurotoxicity in mice, 2) Investigate mechanisms of Mn-induced REST reduction and the protective effects of REST against Mn neurotoxicity via upregulation of TH, CAT and Bcl-2, and 3) Test if DAergic REST is a critical mediator of TX-induced neuroprotection against Mn toxicity. The outcome of the study will provide critical information on the role of REST in DAergic neuronal function, Mn toxicity and TX-induced neuroprotection against Mn toxicity. The results also greatly contribute to the development of `neuroSERMs' to treat NDs associated with DAergic injury, such as manganism and potentially 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: 2025 ( Subtotal = $440,960 )
2025	2025	FLORIDA A & M UNIVERSITY	1700 LEE HALL DR #201	TALLAHASSEE	FL	32307	LEON	USA	Environmental Health	000	5	5/13/2025	NON-COMPETING CONTINUATION	$440,960
														Subtotal = $440,960

Issue Date FY: 2024 ( Subtotal = $440,960 )
2024	2024	FLORIDA A & M UNIVERSITY	1700 LEE HALL DR #201	TALLAHASSEE	FL	32307	LEON	USA	Environmental Health	000	4	5/29/2024	NON-COMPETING CONTINUATION	$440,960
														Subtotal = $440,960

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	FLORIDA A & M UNIVERSITY	1500 WAHNISH WAY	TALLAHASSEE	FL	32307	LEON	USA	Environmental Health	000	3	5/17/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $484,458 )
2022	2022	FLORIDA A & M UNIVERSITY	1500 WAHNISH WAY	TALLAHASSEE	FL	32307	LEON	USA	Environmental Health	000	3	5/18/2022	NON-COMPETING CONTINUATION	$484,458
														Subtotal = $484,458

Issue Date FY: 2021 ( Subtotal = $476,082 )
2021	2021	FLORIDA A & M UNIVERSITY	1500 WAHNISH WAY	TALLAHASSEE	FL	32307	LEON	USA	Environmental Health	000	2	6/1/2021	NON-COMPETING CONTINUATION	$476,082
														Subtotal = $476,082

Issue Date FY: 2020 ( Subtotal = $543,163 )
2020	2020	FLORIDA A & M UNIVERSITY	1500 WAHNISH WAY	TALLAHASSEE	FL	32307	LEON	USA	Environmental Health	000	1	8/7/2020	NEW	$543,163
														Subtotal = $543,163

Grand Total All Awards = $2,385,623

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Mechanisms associated with neuroprotection from Mn-induced neurotoxicity.

Award Number: R01ES031282

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: 08/10/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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