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Mitochondrial Ion Channels in Hypoxic Neurons

Award Number: R37NS045876
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: 06/01/2004
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Mitochondrial Ion Channels in Hypoxic Neurons - Transient global ischemia in rodents (2 vessel occlusion in mice, 2VO) induces delayed death of hippocampal CA1 neurons and is a model for human ischemic brain injury and long lasting hippocampal memory deficits. Events that occur before neuronal death include caspase and pro-apoptotic Bcl-2 family member (Bax) activation, cleavage of the anti-death Bcl-2 family protein Bcl-xL, cellular Ca2+ dysregulation and large conductance mitochondrial channel activity. The opening of a large conductance, Ca2+ dependent, inner mitochondrial membrane channel occurs early during the injury phase, therefore the identification and targeting of this inner membrane channel has long been an important goal of both basic research and clinical communities. The inner membrane channel is known as the mitochondrial permeability transition pore (mPTP). It is activated by neuronal Ca2+ dysregulation and by the binding of the mitochondrial peptidyl-prolyl cis-trans isomerase cyclophilin D (CypD). It has been reported that CypD binds to the stator region of the ATP synthase at the OSCP subunit. CypD binding is inhibited by the well-known mPTP inhibitor cyclosporine A (CsA), which attenuates mPT channel activation. During the previous funding period, we were the first to demonstrate that the ATP synthase membrane-embedded c-subunit forms the largest known channel of the mPTP, the ATP synthase c-subunit leak channel (ACLC), and we showed that CsA inhibits ACLC activity by binding within the ATP synthase F1/stator portion because channel inhibition fails to occur when the membrane portions of the ATP synthase are chemically stripped of the F1/stator components. We also reported that Dexpramipexole (Dex) is a safe modulator of ATP synthase leak that binds directly to OSCP/subunit b on the stator complex. Dex ameliorates disease in a neurodevelopmental brain disorder. In this current renewal we will focus on the ACLC as the target to inhibit mPTP opening and death. By mutation of the c-subunit to reduce channel activity, we will inhibit ACLC opening and prevent mitochondrial permeability transition (mPT) during glutamate excitotoxicity in neurons and in vivo ischemic brain injury in mice. We will determine if memory loss, a severe, long lasting effect of transient global ischemia in rodents and humans, will be prevented by this genetic strategy.


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 = $383,111 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	12/10/2024	NON-COMPETING CONTINUATION	$383,111
														Subtotal = $383,111

Issue Date FY: 2024 ( Subtotal = $412,910 )
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	20	12/1/2023	NON-COMPETING CONTINUATION	-$29,799
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	20	5/10/2024	NON-COMPETING CONTINUATION	$29,799
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	11/24/2023	NON-COMPETING CONTINUATION	$412,910
														Subtotal = $412,910

Issue Date FY: 2023 ( Subtotal = $508,921 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	19	4/28/2023	NON-COMPETING CONTINUATION	$64,704
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	19	1/31/2023	NON-COMPETING CONTINUATION	$36,097
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	12/8/2022	NON-COMPETING CONTINUATION	$324,878
2023	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	18	4/28/2023	COMPETING CONTINUATION	$83,242
														Subtotal = $508,921

Issue Date FY: 2022 ( Subtotal = $409,312 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	18	12/27/2021	COMPETING CONTINUATION	$132
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	12/9/2021	COMPETING CONTINUATION	$409,312
2022	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	17	12/27/2021	NON-COMPETING CONTINUATION	-$132
														Subtotal = $409,312

Issue Date FY: 2020 ( Subtotal = $365,160 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	6/15/2020	NON-COMPETING CONTINUATION	$365,160
														Subtotal = $365,160

Issue Date FY: 2019 ( Subtotal = $365,160 )
2019	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	16	6/19/2019	NON-COMPETING CONTINUATION	$365,160
2019	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	4/11/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $365,160

Issue Date FY: 2018 ( Subtotal = $385,160 )
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	6/15/2018	EXTENSION WITH OR WITHOUT FUNDS	$385,160
														Subtotal = $385,160

Issue Date FY: 2017 ( Subtotal = $416,250 )
2017	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	6/16/2017	NON-COMPETING CONTINUATION	$416,250
														Subtotal = $416,250

Issue Date FY: 2016 ( Subtotal = $416,250 )
2016	2016	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	6/8/2016	NON-COMPETING CONTINUATION	$416,250
														Subtotal = $416,250

Issue Date FY: 2015 ( Subtotal = $416,250 )
2015	2015	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	6/17/2015	NON-COMPETING CONTINUATION	$416,250
														Subtotal = $416,250

Issue Date FY: 2014 ( Subtotal = $416,250 )
2014	2014	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	8/21/2014	COMPETING CONTINUATION	$416,250
														Subtotal = $416,250

Grand Total All Awards = $4,494,734

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Mitochondrial Ion Channels in Hypoxic Neurons

Award Number: R37NS045876

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: 06/01/2004

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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