Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Mechanism of manganese-induced impairment of astrocytic glutamate transporters

Award Number: R01ES024756
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: 11/14/2016
PERIOD OF PERFORMANCE END DATE: 06/30/2022

Group Awards By:

View Award Description

Mechanism of manganese-induced impairment of astrocytic glutamate transporters - DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a neurodegenerative disease which can be ascribed in only 10-20% of cases to genetics. Epidemiological evidence suggests that PD is more common in rural areas, where its increased prevalence is associated with the use of pesticides, herbicides and heavy metals, including manganese (Mn). Chronic exposure to high Mn levels causes manganism, which has multiple shared features with PD, but the mechanisms by which Mn induces neurotoxicity have yet to be fully established. Mn decreases expression of glutamate transporter GLT-1, which regulates synaptic glutamate levels and prevents excitotoxic neuronal injury. Our preliminary studies indicate that the transcription factor yin yang 1 (YY1) plays a critical role in the effect of Mn on GLT-1. Accordingly, delineating the precise mechanism of Mn-induced dysregulation of GLT-1 expression is critical in advancing our understanding of Mn neurotoxicity. Moreover, identifying molecular targets of Mn-induced GLT-1 dysfunction will have broad applicability, since a plethora of neurodegenerative diseases, such as PD, Alzheimer's disease and amyotrophic lateral sclerosis are associated with perturbed glutamate homeostasis secondary to GLT-1 dysfunction. Thus, our long-term goal is to understand the mechanisms involved in the regulation of GLT-1 expression in relation to the excitotoxic neurodegeneration. Our immediate objective is to determine how YY1 regulates Mn-induced repression of GLT-1. Here, we present preliminary data characterizing a previously unknown role of YY1 in Mn-induced repression of GLT-1. Among our findings, we determined that Mn increases YY1 expression via NF-κB. In addition, epigenetic modifier histone deacetylases (HDACs) serve as co-repressors of YY1, and HDAC inhibitors (HDACi) reverse Mn-induced repression of GLT-1 promoter activity. Given these observations, we hypothesize that Mn-induced GLT-1 repression by NF-κB-dependent YY1 activation, with HDACs acting as co-repressors, mediates Mn-induced neurotoxicity. Our proposed work is the first in the field to explore the effect of Mn on GLT-1 expression via YY1 at the transcriptional level. Our hypothesis will be tested in the following specific aims: 1) Determine if astrocytic YY1 mediates Mn-induced neurotoxicity by impairing GLT-1 expression and function using astrocyte-specific YY1 conditional knockout mice, 2) Delineate the molecular mechanisms of Mn-induced activation of YY1 and its role in regulating GLT-1 function in vitro using primary astrocytes, and 3) Test if Mn- enhanced YY1 expression and the ensuing GLT-1 repression are regulated by HDAC epigenetic modification. Our studies will provide novel insights into the mechanism(s) underlying the role of the YY1 pathway in Mn-induced repression of GLT-1 function and Mn-induced neurotoxicity. Moreover, the outcome of this study will offer novel therapeutic strategies for neurodegenerative diseases associated with impairment in GLT-1 function and excitotoxicity.


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: 2023 ( Subtotal = -$84,173 )
2023	2019	FLORIDA A & M UNIVERSITY	1700 LEE HALL DR #201	TALLAHASSEE	FL	32307	LEON	USA	Environmental Health	000	6	11/8/2022	NON-COMPETING CONTINUATION	-$84,173
														Subtotal = -$84,173

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	FLORIDA A & M UNIVERSITY	1500 WAHNISH WAY	TALLAHASSEE	FL	32307	LEON	USA	Environmental Health	000	6	7/14/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $412,106 )
2019	2019	FLORIDA A & M UNIVERSITY	1500 WAHNISH WAY	TALLAHASSEE	FL	32307	LEON	USA	Environmental Health	000	6	7/15/2019	NON-COMPETING CONTINUATION	$412,106
														Subtotal = $412,106

Issue Date FY: 2018 ( Subtotal = $412,106 )
2018	2018	FLORIDA A & M UNIVERSITY	1500 WAHNISH WAY	TALLAHASSEE	FL	32307	LEON	USA	Environmental Health	001	5	7/23/2018	SUPPLEMENT FOR EXPANSION	$92,796
2018	2018	FLORIDA A & M UNIVERSITY	1500 WAHNISH WAY	TALLAHASSEE	FL	32307	LEON	USA	Environmental Health	000	5	6/21/2018	NON-COMPETING CONTINUATION	$319,310
														Subtotal = $412,106

Issue Date FY: 2017 ( Subtotal = $319,310 )
2017	2017	FLORIDA A & M UNIVERSITY	1500 WAHNISH WAY	TALLAHASSEE	FL	32307	LEON	USA	Environmental Health	004	4	6/22/2017	NON-COMPETING CONTINUATION	$319,310
2017	2016	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Environmental Health	000	2	11/15/2016	NON-COMPETING CONTINUATION	-$319,310
2017	2016	FLORIDA A & M UNIVERSITY	1500 WAHNISH WAY	TALLAHASSEE	FL	32307	LEON	USA	Environmental Health	003	3	1/23/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$85,931
2017	2016	FLORIDA A & M UNIVERSITY	1500 WAHNISH WAY	TALLAHASSEE	FL	32307	LEON	USA	Environmental Health	001	3	11/16/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$319,310
2017	2015	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Environmental Health	002	1	1/23/2017	NEW	-$85,931
														Subtotal = $319,310

Issue Date FY: 2016 ( Subtotal = $319,310 )
2016	2016	MEHARRY MEDICAL COLLEGE	1005 D B TODD BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Environmental Health	000	2	6/22/2016	NON-COMPETING CONTINUATION	$319,310
														Subtotal = $319,310

Issue Date FY: 2015 ( Subtotal = $329,229 )
2015	2015	MEHARRY MEDICAL COLLEGE	1005 D B TODD BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Environmental Health	000	1	8/12/2015	NEW	$329,229
														Subtotal = $329,229

Grand Total All Awards = $1,707,888

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Mechanism of manganese-induced impairment of astrocytic glutamate transporters

Award Number: R01ES024756

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: 11/14/2016

PERIOD OF PERFORMANCE END DATE: 06/30/2022

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer