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Vesicular modulation of dopamine neuron toxicity

Award Number: R01ES023839
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: 11/17/2014
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Vesicular modulation of dopamine neuron toxicity - Abstract The Miller laboratory has been conducting research on the divergent nature of dopamine in neurons for over two decades. Dopamine is an essential neurotransmitter/neuromodulator, but at the same time it represents a potential source of endogenous toxicity. Data from our laboratory and others have clearly demonstrated that improperly stored dopamine, via altered function of the vesicular monoamine transporter (VMAT2) can induce progressive nigrostriatal dopamine neurodegeneration that is strikingly similar to idiopathic Parkinson’s disease. The synthesis, packaging, and degradation of dopamine (i.e. homeostasis) is thus tightly regulated to minimize the potential for toxicity. In the previous funding period, the laboratory provided the first evidence that the synaptic vesicle glycoprotein 2C (SV2C) was a key modulator of vesicular dopamine homeostasis. We demonstrated that SV2C regulates synaptic dopamine release and its expression is altered in human Parkinson’s disease brain tissue. In April, 2020 another laboratory identified SV2C in a large Parkinson’s disease GWAS firmly positioning the protein as a key player in Parkinson’s disease pathogenesis. New preliminary data from our laboratory indicate that SV2C can confer resistance to MPTP and that it prevents leakage of dopamine from the vesicle. These data serve as the basis of our hypothesis that SV2C, through its ability to retain dopamine within synaptic vesicles, confers resistance to dopamine neurotoxicity. We will test this hypothesis through the following specific aims: Aim 1, to examine the mechanisms by which SV2C regulates vesicular dopamine homeostasis and mediates toxicant-induced neurotoxicity. Aim 2, to determine whether introducing the evolutionarily advanced SV2 proteins into the model organism C. elegans can confer protection against dopaminergic toxicity. Aim 3, to determine the functional properties of SV2C in mice. Aim 4, to determine the role of SV2C in PD-related pathogenesis (synuclein-based and toxicant-induced) in mice. Completion of the above specific aims will provide critical information on the role of SV2C in dopamine neuron function, vulnerability to chemicals suspected in the development of Parkinson’s disease, and its potential as a target of therapeutic intervention.


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 = $475,682 )
2025	2025	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Environmental Health	000	10	1/13/2025	NON-COMPETING CONTINUATION	$475,682
														Subtotal = $475,682

Issue Date FY: 2024 ( Subtotal = $475,682 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Environmental Health	000	9	12/28/2023	NON-COMPETING CONTINUATION	$475,682
														Subtotal = $475,682

Issue Date FY: 2023 ( Subtotal = $471,551 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Environmental Health	000	8	1/13/2023	NON-COMPETING CONTINUATION	$471,551
														Subtotal = $471,551

Issue Date FY: 2022 ( Subtotal = $785,429 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Environmental Health	000	7	12/13/2021	NON-COMPETING CONTINUATION	$472,097
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Environmental Health	003	7	6/27/2022	SUPPLEMENT FOR EXPANSION	$313,332
2022	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Environmental Health	002	6	4/19/2022	COMPETING CONTINUATION	$3,265
2022	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Environmental Health	001	5	4/19/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$3,265
														Subtotal = $785,429

Issue Date FY: 2021 ( Subtotal = $472,657 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Environmental Health	004	6	8/7/2021	COMPETING CONTINUATION	$27,839
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Environmental Health	002	6	3/17/2021	COMPETING CONTINUATION	$472,657
2021	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Environmental Health	000	5	11/17/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2021	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Environmental Health	003	5	8/7/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$27,839
2021	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Environmental Health	001	5	3/11/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $472,657

Issue Date FY: 2019 ( Subtotal = $408,947 )
2019	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Environmental Health	004	5	8/19/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$454,547
2019	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Environmental Health	001	5	5/29/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$408,947
2019	2018	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Environmental Health	000	4	5/29/2019	NON-COMPETING CONTINUATION	$0
2019	2018	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Environmental Health	003	4	8/19/2019	SUPPLEMENT FOR EXPANSION	-$386,618
2019	2018	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Environmental Health	002	4	8/19/2019	NON-COMPETING CONTINUATION	-$67,929
														Subtotal = $408,947

Issue Date FY: 2018 ( Subtotal = $795,843 )
2018	2018	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Environmental Health	000	4	11/29/2017	NON-COMPETING CONTINUATION	$409,225
2018	2018	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Environmental Health	001	4	8/27/2018	SUPPLEMENT FOR EXPANSION	$386,618
														Subtotal = $795,843

Issue Date FY: 2017 ( Subtotal = $372,837 )
2017	2017	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Environmental Health	000	3	11/1/2016	NON-COMPETING CONTINUATION	$348,484
2017	2017	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Environmental Health	001	3	7/6/2017	SUPPLEMENT FOR EXPANSION	$24,353
														Subtotal = $372,837

Issue Date FY: 2016 ( Subtotal = $348,713 )
2016	2016	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Environmental Health	000	2	11/16/2015	NON-COMPETING CONTINUATION	$348,713
														Subtotal = $348,713

Issue Date FY: 2015 ( Subtotal = $348,921 )
2015	2015	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Environmental Health	000	1	11/17/2014	NEW	$348,921
														Subtotal = $348,921

Grand Total All Awards = $4,956,262

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Vesicular modulation of dopamine neuron toxicity

Award Number: R01ES023839

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: 11/17/2014

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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