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Novel presynaptic agents to prevent glutamate-induced neural injury

Award Number: R01NS113955
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: 12/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Novel presynaptic agents to prevent glutamate-induced neural injury - Temporal lobe epilepsy is the most common form of focal (partial) or location related epilepsy. It affects about 60 percent of all people with epilepsy and can occur at any age. The kainic acid model of temporal lobe epilepsy has greatly contributed to the understanding of the molecular, cellular and pharmacological mechanisms underlying epileptogenesis. This model presents with neuropathological features that are seen in patients with temporal lobe epilepsy. There are many potential causes, and often the exact cause is unknown. Excessive presynaptic glutamate (Glu) release causes excessive stimulation of NMDA receptors that is implicated in many CNS disorders that result in acute and chronic neurodegeneration including epilepsy. Mechanisms to reduce excessive synaptic Glu release under these conditions could potentially prevent/reduce excitotoxic damage to vulnerable hippocampal neurons. Current treatment options to prevent excessive Glu release are limited and most post-synaptic interventions in human studies have been disappointing because of poor efficacy or unacceptable side effects. Under normal conditions, maintenance of synaptic cytoplasmic Glu levels (~2mM) required for vesicular filling is via α-ketoglutarate-derived Glu synthesis. The scientific premise for the proposed project is that glutamine (Gln) is a precursor for Glu synthesis under high synaptic activity because under increased excitatory activity Gln is imported into axon terminals from glia where it is synthesized. Hence, Na+-dependent Gln import into neurons from glia to replenish synaptic cytoplasmic Glu stores under high synaptic activity is a potential novel target to prevent excessive Glu release under excitotoxic conditions. We have recently discovered a neuronal activity-regulated Gln transporter expressed in excitatory synapses that is potently inhibited by riluzole, a benzothiazole compound that is believed to inhibit excessive Glu release from synapses. A critical barrier to progress in understanding the presynaptic mechanisms involved in excessive Glu release has been the lack of molecular information about the transporter that mediates K+-stimulated, activity-regulated Gln import into excitatory synapses. In addition, the role of activity-regulated Gln transport in synapses to support excessive Glu release and neural injury has not been revealed and potential therapeutic agents that target activity-regulated Gln transport in synapses and that are neuroprotective, more selective, brain penetrant, with fewer side effects than riluzole have not been developed. This project has important implications in advancing basic understanding of the neurobiology of excessive synaptic release of Glu, Glu/Gln cycling between neuronal and glial synapses, and Glu-induced neuronal excitotoxicity. Resolution of this missing link of the role for activity-regulated Gln transport in synaptic Glu synthesis in hippocampal neurons provide the basis for studies in in vitro and in vivo models of excessive Glu release to better understand the fundamental presynaptic mechanisms that lead to presynaptic Glu-induced acute and chronic neurodegenerative diseases.


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 = $313,433 )
2024	2024	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/17/2024	NON-COMPETING CONTINUATION	$22,619
2024	2024	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/13/2023	NON-COMPETING CONTINUATION	$290,814
														Subtotal = $313,433

Issue Date FY: 2023 ( Subtotal = $323,115 )
2023	2023	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	2/2/2023	NON-COMPETING CONTINUATION	$32,311
2023	2023	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/20/2022	NON-COMPETING CONTINUATION	$290,804
														Subtotal = $323,115

Issue Date FY: 2022 ( Subtotal = $323,104 )
2022	2022	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/31/2022	NON-COMPETING CONTINUATION	$32,311
2022	2022	LOUISIANA STATE UNIVERSITY SYSTEM	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/19/2021	NON-COMPETING CONTINUATION	$290,793
														Subtotal = $323,104

Issue Date FY: 2021 ( Subtotal = $326,607 )
2021	2021	LOUISIANA STATE UNIVERSITY SYSTEM	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/11/2021	NON-COMPETING CONTINUATION	$32,662
2021	2021	LOUISIANA STATE UNIVERSITY SYSTEM	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/25/2020	NON-COMPETING CONTINUATION	$293,945
														Subtotal = $326,607

Issue Date FY: 2020 ( Subtotal = $336,848 )
2020	2020	LOUISIANA STATE UNIVERSITY SYSTEM	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/19/2019	NEW	$336,848
														Subtotal = $336,848

Grand Total All Awards = $1,623,107

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Novel presynaptic agents to prevent glutamate-induced neural injury

Award Number: R01NS113955

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: 12/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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