Thursday, November 21, 2024 11/21/2024

Mechanisms of Manganese Neurotoxicity

Award Number: R01ES010563
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 Our understanding of how chronic Mn may trigger or promote central nervous system (CNS) morbidities remains fragmentary. Here, we seek to continue our studies into the mechanisms of Mn neurotoxicity by focusing on chronic exposures. Acute Mn cellular neurotoxicity occurs by alterations in cell signaling pathways that normally rely on Mn for their function, e.g., insulin-like growth factor (IGF)/insulin metabolic signaling pathway (IIS), and the highly interconnected mTOR (mTORC1 and mTORC2), AKT and ATM/p53 metabolic signaling systems. Existing research strongly supports a mechanism of Mn neurotoxicity related to the fact that Mn-dependent enzymes are situated at key regulatory nodes in these metabolic signaling pathways. New data support role for two other signaling systems linked to healthy aging in chronic Mn neurotoxicity, the eIF2 and Sirtuin (SIRT) signaling pathways. It is noteworthy that real-life Mn exposures in the human population occur over an extended period, months to years, involving lower extracellular or intracellular levels of Mn not associated with cell death in acute neurotoxicity studies. Mechanistic details underlying the biological changes that occur under chronic Mn intoxication remain elusive and thus warrant further investigation. Moreover, it is highly likely that persistent Mn effects are in a complex interplay with genetics, sex and age. Therefore, we seek to test the overarching hypothesis that chronic Mn neurotoxicity is caused by long-term elevated Mn altering the activity of neuronal cell signaling systems for which Mn normally acts as an essential co-factor that regulate healthy aging. To address this overarching hypothesis we have designed three highly meritorious Specific Aims, namely (1) determine the evolution of genetic pathways altered as Mn exposure extends from acute to chronic, and whether any such effects are persistent after cessation of chronic Mn overload, (2) evaluate the concurrent and persistent functional consequences of acute versus chronic Mn exposures and the influence of neural cell type, neurotransmitter- type, and genetic sex on the magnitude versus types of genetic pathways and functional outcomes altered, and (3) Explore the mechanistic basis of chronic/persistent Mn neurotoxicity phenotypes via metabolic analysis, with pharmacological and genetic manipulation of signaling and metabolic pathways in C. elegans and hiPSC neural model systems. Our highly interactive experimental design brings to bear innovative and complementary expertise to assess shared genetic networks and functional outcomes of Mn-induced chronic neurotoxicity with translation from C. elegans to humans.


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	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Environmental Health	001	23	10/17/2024	COMPETING CONTINUATION	$61,708
2025	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Environmental Health	000	22	10/17/2024	NON-COMPETING CONTINUATION	-$61,708
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $695,061 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Environmental Health	001	23	1/31/2024	COMPETING CONTINUATION	$695,061
2024	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Environmental Health	000	22	1/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $695,061

Issue Date FY: 2022 ( Subtotal = $597,445 )
2022	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Environmental Health	000	22	4/25/2022	NON-COMPETING CONTINUATION	$597,445
														Subtotal = $597,445

Issue Date FY: 2021 ( Subtotal = $597,445 )
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Environmental Health	000	21	3/22/2021	NON-COMPETING CONTINUATION	$597,445
														Subtotal = $597,445

Issue Date FY: 2020 ( Subtotal = $597,445 )
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Environmental Health	000	20	4/7/2020	NON-COMPETING CONTINUATION	$597,445
														Subtotal = $597,445

Issue Date FY: 2019 ( Subtotal = $597,445 )
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Environmental Health	004	19	7/12/2019	NON-COMPETING CONTINUATION	$597,445
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Environmental Health	002	17	6/28/2019	COMPETING CONTINUATION	-$150,718
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Environmental Health	000	17	2/8/2019	COMPETING CONTINUATION	-$28,170
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Environmental Health	003	18	6/28/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$150,718
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Environmental Health	001	18	2/8/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$28,170
														Subtotal = $597,445

Issue Date FY: 2018 ( Subtotal = $614,195 )
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Environmental Health	003	17	9/22/2018	COMPETING CONTINUATION	$505
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Environmental Health	001	17	3/5/2018	COMPETING CONTINUATION	$614,195
2018	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Environmental Health	002	16	9/22/2018	NON-COMPETING CONTINUATION	-$505
2018	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Environmental Health	000	16	2/28/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $614,195

Issue Date FY: 2017 ( Subtotal = $565,220 )
2017	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Environmental Health	000	16	11/1/2016	NON-COMPETING CONTINUATION	$565,220
														Subtotal = $565,220

Issue Date FY: 2016 ( Subtotal = $954,883 )
2016	2016	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Environmental Health	000	15	11/16/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$954,883
														Subtotal = $954,883

Issue Date FY: 2015 ( Subtotal = $958,449 )
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Environmental Health	000	14	10/31/2014	NON-COMPETING CONTINUATION	$862,605
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Environmental Health	001	14	1/26/2015	NON-COMPETING CONTINUATION	$95,844
														Subtotal = $958,449

Issue Date FY: 2014 ( Subtotal = $1,030,778 )
2014	2014	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Environmental Health	002	13	4/9/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$53,435
2014	2014	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Environmental Health	000	13	12/6/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$551,069
2014	2014	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Environmental Health	001	13	3/4/2014	SUPPLEMENT FOR EXPANSION	$426,274
														Subtotal = $1,030,778

Issue Date FY: 2013 ( Subtotal = $577,194 )
2013	2013	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Environmental Health	000	12	10/22/2012	COMPETING CONTINUATION	$577,194
2013	2011	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Environmental Health	001	11	10/22/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $577,194

Issue Date FY: 2011 ( Subtotal = $329,420 )
2011	2011	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Environmental Health	001	11	6/9/2011	NON-COMPETING CONTINUATION	$29,947
2011	2011	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Environmental Health	000	11	12/28/2010	NON-COMPETING CONTINUATION	$299,473
														Subtotal = $329,420

Issue Date FY: 2010 ( Subtotal = $332,747 )
2010	2010	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Environmental Health	001	10	2/2/2010	NON-COMPETING CONTINUATION	$30,250
2010	2010	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Environmental Health	000	10	12/4/2009	NON-COMPETING CONTINUATION	$302,497
														Subtotal = $332,747

Issue Date FY: 2009 ( Subtotal = $336,108 )
2009	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Environmental Health	001	9	3/20/2009	NON-COMPETING CONTINUATION	$33,611
2009	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Environmental Health	000	9	1/22/2009	NON-COMPETING CONTINUATION	$302,497
														Subtotal = $336,108

Issue Date FY: 2008 ( Subtotal = $336,108 )
2008	2008	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Environmental Health	000	8	12/17/2007	NON-COMPETING CONTINUATION	$336,108
														Subtotal = $336,108

Issue Date FY: 2007 ( Subtotal = $344,719 )
2007	2007	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Environmental Health	000	7	1/1/2007	COMPETING CONTINUATION	$344,719
														Subtotal = $344,719

Grand Total All Awards = $10,549,392

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Mechanisms of Manganese Neurotoxicity

Award Number: R01ES010563

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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