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Altered Hippocampal Neurogenesis and Cognition via Maneb-mediated Changes in the Thiol Redox Proteome.

Award Number: R01ES027593
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: 03/01/2017
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Altered Hippocampal Neurogenesis and Cognition via Maneb-mediated Changes in the Thiol Redox Proteome. - The overall goal of this proposal is to elucidate the thiol redox mechanisms that alter neurodevelopment, which can exacerbate cognitive dysfunction in Down syndrome (DS). Down syndrome (DS) is the most common genetic cause of intellectual disability. Importantly, the extent of intellectual disability is highly variable, and parents of affected individuals are often aware of DS during pregnancy. This creates a window of opportunity to improve outcomes through identification of environmental factors and associated mechanisms impacting early development in DS. Preliminary data and reports from our laboratory and others demonstrate that cells from DS individuals exhibit distorted proteostasis, enhanced oxidative stress, and altered metabolism. We hypothesize that these are linked through atypical thiol redox systems in DS cells. This increases vulnerability to thiol-reactive xenobiotics through dysregulation of central carbon metabolism, modifying stem cell fate decisions via altered regulation of Wnt/β-catenin signaling as a mechanism contributing to cognitive dysfunction. Our prior results show that the environmental toxicant, maneb (MB), a neurotoxic dithiocarbamate fungicide, impairs proteostasis, increases oxidative stress and displays greater toxicity in DS cells compared to euploid controls. MB also modifies mitochondrial function, central carbon metabolism and our new preliminary data show that DS cells display significant baseline alterations in the Wnt signaling pathway. Wnt signaling is a vital cell signaling conduit critical for both stem cell maintenance and neurodevelopment. Therefore, elucidating the environmental mechanisms impacting DS development, e.g. Wnt signaling and oxidative stress, will provide a foundation to prioritize environmental chemical surveillance in DS neurodevelopment. Disruption of cellular thiol redox systems, e.g. thiol redox proteome, is a key feature of oxidative stress. This mechanism is also critical for embryonic development, where mitochondrially-derived reactive oxygen species (ROS) trigger stem cells to differentiate. Thus, the approach detailed below will include thiol-reactive toxicants (TRT) as an innovative means to study Gene-Environment interactions affecting neurodevelopment in a special population, DS. This proposal involves three Specific Aims and makes use of a powerful library of euploid and trisomy 21 induced pluripotent stem cells (iPSC) and directed differentiation protocols to investigate the role of thiol redox signaling in the effects of TRT on stem cells derived from DS individuals, and how these exposures alter specific pathways (Wnt and central carbon metabolism) during neurodevelopment. In Specific Aim 1 we will determine if trisomy 21-mediated Wnt dysfunction is exacerbated by TRT exposure, resulting in aberrant iPSC differentiation. Western blotting, qRT-PCR, chemical tools and single cell transcriptomics will be used to interrogate this aim. Specific Aim 2 is designed to study the impact of TRT exposure on the thiol redox proteome and identify mechanistic targets involved in aberrant differentiation. In Specific Aim 3 we will utilize metabolic approaches like metabolomics and extracellular flux analyses to correlate Wnt dysfunction and redox proteomic alterations to metabolic alterations and developmental outcomes. Together, the novel research proposed here will fill a critical gap in knowledge with regard to neurodevelopmental impacts of thiol reactive toxicants in DS and how these exposures can alter neurogenesis, potentially contributing to cognitive variability. Finally, the studies described here are an innovative and data-driven extension of my funded research exploring further into new mechanisms, e.g. Wnt and thiol redox signaling, by which exposures can alter critical neurodevelopmental processes in DS.


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: 2026 ( Subtotal = $611,887 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Environmental Health	000	7	3/10/2026	EXTENSION WITH OR WITHOUT FUNDS	$611,887
														Subtotal = $611,887

Issue Date FY: 2023 ( Subtotal = $1,724,424 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Environmental Health	000	6	3/2/2023	COMPETING CONTINUATION	$1,724,424
														Subtotal = $1,724,424

Issue Date FY: 2022 ( Subtotal = -$5,417 )
2022	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Environmental Health	000	5	8/23/2022	NON-COMPETING CONTINUATION	-$5,417
														Subtotal = -$5,417

Issue Date FY: 2021 ( Subtotal = $380,240 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Environmental Health	000	5	2/24/2021	NON-COMPETING CONTINUATION	$380,240
														Subtotal = $380,240

Issue Date FY: 2020 ( Subtotal = $382,573 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Environmental Health	000	4	2/24/2020	NON-COMPETING CONTINUATION	$382,573
														Subtotal = $382,573

Issue Date FY: 2019 ( Subtotal = $409,678 )
2019	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Environmental Health	000	3	3/1/2019	NON-COMPETING CONTINUATION	$409,678
														Subtotal = $409,678

Issue Date FY: 2018 ( Subtotal = $1,125,162 )
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Environmental Health	001	2	8/27/2018	SUPPLEMENT FOR EXPANSION	$388,627
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Environmental Health	000	2	2/22/2018	NON-COMPETING CONTINUATION	$473,078
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Environmental Health	002	2	9/24/2018	SUPPLEMENT FOR EXPANSION	$263,457
														Subtotal = $1,125,162

Issue Date FY: 2017 ( Subtotal = $485,186 )
2017	2017	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Environmental Health	000	1	2/14/2017	NEW	$485,186
														Subtotal = $485,186

Grand Total All Awards = $5,113,733

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Altered Hippocampal Neurogenesis and Cognition via Maneb-mediated Changes in the Thiol Redox Proteome.

Award Number: R01ES027593

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: 03/01/2017

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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