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Transport Cycle and Inhibition of Human Na+-dicarboxylate Cotransporter NaDC3

Award Number: R01NS108151
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Transport Cycle and Inhibition of Human Na+-dicarboxylate Cotransporter NaDC3 - PROJECT SUMMARY The human high-affinity Na+-driven dicarboxylate transporter NaDC3 plays critical roles in physiology. The gene of the transporter, SLC13A3, is expressed in the brain as well as other tissues. Located in the plasma membrane, the transporter imports various dicarboxylates into the cell, including succinate, a-ketoglutarate (aKG) and N- acetyl-aspartate (NAA). In addition to being intermediates of the TCA cycle, dicarboxylates imported by NaDC3 also function as signaling molecules in the cell. In the brain, NAA functions as a precursor for the synthesis of both neurohormones and lipids and as an osmolyte in cell volume regulation and in axon-glial signaling. The transporter is involved in a number of disorders, including the lethal Canavan disease, an early-onset CNS condition with “spongiform” vacuolation of white matter in the brain, caused by the overloading of NAA in glial cells. Inhibition of the dicarboxylate transporter is a possible treatment, and small-molecule inhibitors have been identified. In this project, we aim (1) to characterize the structural basis of NaDC3’s substrate specificity. (2) to study inhibition mechanisms. (3) to investigate the conformational changes between the outward- and inward- facing transitions. (4) to understand the sodium—substrate energy coupling. By accomplishing these aims, we will be able to understand the molecular mechanism of the human NaDC3 over its complete transport cycle, including its Co—Ci conformational transition and substrate—sodium coupling mechanism. Comparison of the inhibitor-binding sites in NaDC3 and other proteins will aid in the design of NaDC3 specific inhibitors to help patients suffering from Canavan disease.


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 = $488,265 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	12/17/2025	NON-COMPETING CONTINUATION	$488,265
														Subtotal = $488,265

Issue Date FY: 2025 ( Subtotal = $488,265 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	1/15/2025	NON-COMPETING CONTINUATION	$488,265
2025	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	1/14/2025	COMPETING CONTINUATION	$10,646
2025	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/14/2025	NON-COMPETING CONTINUATION	-$10,646
														Subtotal = $488,265

Issue Date FY: 2024 ( Subtotal = $542,517 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	12/28/2023	COMPETING CONTINUATION	$542,517
2024	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $542,517

Issue Date FY: 2022 ( Subtotal = $484,669 )
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/13/2022	NON-COMPETING CONTINUATION	$484,669
														Subtotal = $484,669

Issue Date FY: 2021 ( Subtotal = $511,340 )
2021	2021	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/15/2021	NON-COMPETING CONTINUATION	$485,981
2021	2021	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	8/19/2021	SUPPLEMENT FOR EXPANSION	$25,359
														Subtotal = $511,340

Issue Date FY: 2020 ( Subtotal = $487,263 )
2020	2020	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/16/2020	NON-COMPETING CONTINUATION	$487,263
														Subtotal = $487,263

Issue Date FY: 2019 ( Subtotal = $488,513 )
2019	2019	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/1/2019	NON-COMPETING CONTINUATION	$488,513
														Subtotal = $488,513

Issue Date FY: 2018 ( Subtotal = $507,106 )
2018	2018	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/24/2018	NEW	$507,106
														Subtotal = $507,106

Grand Total All Awards = $3,997,938

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Transport Cycle and Inhibition of Human Na+-dicarboxylate Cotransporter NaDC3

Award Number: R01NS108151

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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