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Imaging Biomarkers of Neurotoxicity in Welders

Award Number: R01ES021488
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: 02/11/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Imaging Biomarkers of Neurotoxicity in Welders - Abstract Manganese (Mn) is an established neurotoxicant that affects the same motor and cognitive brain pathways affected in Parkinson disease (PD), notably the nigrostriatal system. A large body of research, largely from our collaborative team, demonstrates that Mn-exposed workers have a clinical phenotype which overlaps substantially with PD, including Mn-dose-dependent progressive parkinsonism and nigrostriatal dysfunction on positron emission tomography (PET) brain imaging. In the first five years of the present PET imaging project, we used PET biomarkers of the dopaminergic system in the brain to establish that Mn-exposed workers had lower caudate binding of the PET radioligand 6-[18F]fluoro-L-dopa (FDOPA), as compared to non-exposed workers. These differences remained over five years of follow-up. We also found Mn-dose-dependent upregulation of dopamine type 2 receptor (D2R) binding, as measured by the radioligand [11C](N- methyl)benperidol (NMB), in the substantia nigra, the same region of the brain most dramatically affected in PD. In addition, we found an inverse Mn-dose-response association with thalamic (i.e., extrastriatal) [11C]dihydrotetrabenazine (DTBZ) binding, as well as a decline in DTBZ binding in caudate, putamen, and substantia nigra over time. More recently, our lab found evidence of Mn-induced neuroinflammation (microglial activation) in the brains of deceased Mn miners providing a potential mechanism for the in vivo findings in our welder cohort. This renewal builds on our previous studies by exploring the role of neuroinflammation in Mn- induced dopaminergic neurotoxicity. Our hypothesis is that Mn-induced progressive parkinsonism is a neurodegenerative disorder and is due to Mn-dose-dependent dopaminergic degeneration. We will perform repeat DTBZ and NMB PET imaging in research participants from our longitudinal Mn-exposed worker cohort who have already undergone baseline DTBZ and NMB scans to investigate the association between lifetime cumulative Mn exposure, informed by state-of-the-art neutron activated bone Mn quantication, and annual rate of change in DTBZ and NMB binding. We will also perform N-acetyl-N-(2-[(11)C]methoxybenzyl)-2-phenoxy-5- pyridinamine [(11)C]PBR28 (PBR28) PET imaging in these workers to characterize patterns of microglial activation in the same brain regions, and investigate the relationship between lifetime cumulative Mn exposure and PBR28 binding as a marker of neuroinflammation. We then will explore the role of neuroinflammation as a mediator of Mn-induced striatal degeneration. Finally, we enlarge our cohort to enrich for active workers and will perform longitudinal PET imaging to characterize the relation between lifetime cumulative Mn exposure and the annual rate of change in both striatal and extrastriatal binding/uptake of these radioligands between active and retired Mn-exposed workers. Successful completion of these aims will provide a unique opportunity to understand the mechanism of an important environmental nigrostriatal neurotoxicant and potentially inform the understanding of the environmental pathogenesis of 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: 2024 ( Subtotal = $490,249 )
2024	2024	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Environmental Health	000	10	7/2/2024	NON-COMPETING CONTINUATION	$490,249
														Subtotal = $490,249

Issue Date FY: 2023 ( Subtotal = $408,379 )
2023	2023	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Environmental Health	005	9	6/6/2023	NON-COMPETING CONTINUATION	$507,244
2023	2022	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Environmental Health	001	8	2/10/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$526,094
2023	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Environmental Health	003	7	5/18/2023	NON-COMPETING CONTINUATION	-$1
2023	2022	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Environmental Health	004	8	5/18/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$572,063
2023	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Environmental Health	000	7	2/8/2023	NON-COMPETING CONTINUATION	-$624,959
2023	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Environmental Health	002	6	5/18/2023	COMPETING CONTINUATION	-$572,062
														Subtotal = $408,379

Issue Date FY: 2022 ( Subtotal = $624,960 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Environmental Health	001	7	7/4/2022	NON-COMPETING CONTINUATION	$624,960
2022	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Environmental Health	000	6	10/28/2021	COMPETING CONTINUATION	$0
														Subtotal = $624,960

Issue Date FY: 2021 ( Subtotal = $648,694 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Environmental Health	000	6	9/20/2021	COMPETING CONTINUATION	$648,694
														Subtotal = $648,694

Issue Date FY: 2019 ( Subtotal = -$2,029 )
2019	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Environmental Health	000	5	2/26/2019	NON-COMPETING CONTINUATION	-$2,029
														Subtotal = -$2,029

Issue Date FY: 2017 ( Subtotal = $555,497 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Environmental Health	000	5	11/1/2016	NON-COMPETING CONTINUATION	$555,497
														Subtotal = $555,497

Issue Date FY: 2016 ( Subtotal = $586,716 )
2016	2016	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Environmental Health	000	4	11/16/2015	EXTENSION WITH OR WITHOUT FUNDS	$586,716
														Subtotal = $586,716

Issue Date FY: 2015 ( Subtotal = $591,238 )
2015	2015	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Environmental Health	001	3	1/28/2015	NON-COMPETING CONTINUATION	$59,125
2015	2015	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Environmental Health	000	3	11/6/2014	NON-COMPETING CONTINUATION	$532,113
														Subtotal = $591,238

Issue Date FY: 2014 ( Subtotal = $751,178 )
2014	2014	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Environmental Health	003	2	9/4/2014	SUPPLEMENT FOR EXPANSION	$0
2014	2014	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Environmental Health	000	2	11/13/2013	NON-COMPETING CONTINUATION	$531,884
2014	2014	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Environmental Health	002	2	8/28/2014	SUPPLEMENT FOR EXPANSION	$166,104
2014	2014	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Environmental Health	001	2	4/4/2014	NON-COMPETING CONTINUATION	$53,190
														Subtotal = $751,178

Issue Date FY: 2013 ( Subtotal = $612,613 )
2013	2013	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Environmental Health	000	1	12/6/2012	NEW	$612,613
														Subtotal = $612,613

Grand Total All Awards = $5,267,495

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Imaging Biomarkers of Neurotoxicity in Welders

Award Number: R01ES021488

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: 02/11/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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