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Liberation of Intracellular Zinc and Neuronal Cell Death

Award Number: R01NS043277
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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This grant proposal represents the third competitive renewal (Years 16-20) of a highly productive research program investigating fundamental cellular and molecular signaling pathways relevant to human neurodegenerative disorders. Over the last 15 years of funding from this grant, our studies have characterized in detail a signaling cascade connecting the oxidative liberation of intracellular zinc to a neuronal cell death-enabling increase in the plasma membrane insertion of Kv2.1 channels. This process mediates a loss of cytoplasmic potassium, a requisite step for optimal protease and nuclease catalytic activity during programmed and other forms of cell death. In the current funding period (Years 11-15), we have studied the phosphorylation events leading to the syntaxin-dependent exocytotic insertion of Kv2.1 into the neuronal plasma membrane following injury. We also investigated the role of Kv2.1 somatodendritic clusters as dominant membrane channel insertion hubs during apoptosis. Most importantly, we established a novel in vivo neuroprotective approach to stroke injury by developing a cell-permeant peptide that interferes with a critical Kv2.1 interaction with syntaxin. Our work strongly indicates that specifically targeting Kv2.1-facilitated cell death processes can provide mechanistically driven, novel therapeutic strategies for neuroprotection. In this application we propose to decisively move forward with this strategic objective by: (i) characterizing the properties of novel neuroprotective peptides and derived small molecule analogs targeting the syntaxin/Kv2.1 interaction; (ii) establishing prototypical neuroprotective tools aimed at dispersing Kv2.1 somatodendritic clusters, and (iii) devising an innovative neuroprotective strategy that transfers a normally silent gene to neurons, designed to express a Kv2.1-targeted modulatory protein when cells are lethally injured. We thus have adopted three unique and potentially transformative strategies, all based on the premise that cell death-inducing pathways require a set of common conditions to operate optimally. The loss of intracellular potassium via a surge of Kv2.1-mediated ionic currents may constitute a widespread, if not ubiquitous, requirement for programmed cell death in many types of neurons. As such, the experiments described here are aimed at translating the cellular and molecular pathways we have characterized with long-term funding from this grant, into rational therapeutic approaches to neurodegeneration.


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: 2022 ( Subtotal = $569,656 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	7/18/2022	NON-COMPETING CONTINUATION	$569,656
														Subtotal = $569,656

Issue Date FY: 2021 ( Subtotal = $569,656 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	7/27/2021	NON-COMPETING CONTINUATION	$569,656
														Subtotal = $569,656

Issue Date FY: 2020 ( Subtotal = $569,656 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	6/22/2020	NON-COMPETING CONTINUATION	$569,656
														Subtotal = $569,656

Issue Date FY: 2019 ( Subtotal = $870,457 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	17	6/18/2019	NON-COMPETING CONTINUATION	$569,656
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	17	7/19/2019	SUPPLEMENT FOR EXPANSION	$300,801
2019	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	16	1/31/2019	COMPETING CONTINUATION	$38,147
2019	2017	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	1/31/2019	NON-COMPETING CONTINUATION	-$38,147
														Subtotal = $870,457

Issue Date FY: 2018 ( Subtotal = $596,693 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	16	8/31/2018	COMPETING CONTINUATION	$596,693
2018	2017	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	8/29/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $596,693

Issue Date FY: 2017 ( Subtotal = $389,065 )
2017	2017	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	15	6/20/2017	NON-COMPETING CONTINUATION	$389,065
2017	2016	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	14	1/24/2017	EXTENSION WITH OR WITHOUT FUNDS	$20,771
2017	2015	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	1/24/2017	NON-COMPETING CONTINUATION	-$20,771
														Subtotal = $389,065

Issue Date FY: 2016 ( Subtotal = $389,065 )
2016	2016	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	7/11/2016	EXTENSION WITH OR WITHOUT FUNDS	$389,065
														Subtotal = $389,065

Issue Date FY: 2015 ( Subtotal = $389,065 )
2015	2015	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	6/24/2015	NON-COMPETING CONTINUATION	$389,065
														Subtotal = $389,065

Issue Date FY: 2014 ( Subtotal = $391,021 )
2014	2014	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	7/15/2014	NON-COMPETING CONTINUATION	$391,021
														Subtotal = $391,021

Issue Date FY: 2013 ( Subtotal = $393,118 )
2013	2013	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	9/2/2013	COMPETING CONTINUATION	$393,118
2013	2012	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	8/30/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $393,118

Issue Date FY: 2012 ( Subtotal = $324,778 )
2012	2012	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	11/24/2011	NON-COMPETING CONTINUATION	$292,301
2012	2012	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	2/24/2012	NON-COMPETING CONTINUATION	$32,477
														Subtotal = $324,778

Issue Date FY: 2011 ( Subtotal = $324,778 )
2011	2011	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	6/14/2011	NON-COMPETING CONTINUATION	$26,512
2011	2011	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	12/16/2010	NON-COMPETING CONTINUATION	$298,266
														Subtotal = $324,778

Issue Date FY: 2010 ( Subtotal = $328,093 )
2010	2010	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	1/19/2010	NON-COMPETING CONTINUATION	$328,093
														Subtotal = $328,093

Issue Date FY: 2009 ( Subtotal = $331,406 )
2009	2009	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	12/23/2008	COMPETING CONTINUATION	$331,406
														Subtotal = $331,406

Issue Date FY: 2006 ( Subtotal = $344,165 )
2006	2006	UNIVERSITY OF PITTSBURGH	3017 CATHEDRAL OF LEARNING	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/8/2006	NON-COMPETING CONTINUATION	$344,165
														Subtotal = $344,165

Issue Date FY: 2005 ( Subtotal = $352,454 )
2005	2005	UNIVERSITY OF PITTSBURGH	3017 CATHEDRAL OF LEARNING	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/25/2005	NON-COMPETING CONTINUATION	$352,454
														Subtotal = $352,454

Issue Date FY: 2004 ( Subtotal = $352,461 )
2004	2004	UNIVERSITY OF PITTSBURGH	3017 CATHEDRAL OF LEARNING	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/21/2004	NON-COMPETING CONTINUATION	$352,461
														Subtotal = $352,461

Issue Date FY: 2003 ( Subtotal = $470,142 )
2003	2003	UNIVERSITY OF PITTSBURGH	3017 CATHEDRAL OF LEARNING	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1		SUPPLEMENT FOR EXPANSION	$116,687
2003	2003	UNIVERSITY OF PITTSBURGH	3017 CATHEDRAL OF LEARNING	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/17/2003	NON-COMPETING CONTINUATION	$353,455
														Subtotal = $470,142

Issue Date FY: 2002 ( Subtotal = $237,862 )
2002	2002	UNIVERSITY OF PITTSBURGH	3017 CATHEDRAL OF LEARNING	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/30/2002	NEW	$237,862
														Subtotal = $237,862

Grand Total All Awards = $8,193,591

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Liberation of Intracellular Zinc and Neuronal Cell Death

Award Number: R01NS043277

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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