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Targeting the Integrated Stress Response to Protect Oligodendrocyte lineage Cells

Award Number: R01NS034939
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: 12/01/1996
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Targeting the Integrated Stress Response to Protect Oligodendrocyte lineage Cells - The focus of the studies funded by this award over the past two decades has been on the response of oligodendrocytes to inflammation. This work is of critical relevance to the immune-mediated demyelinating disorder multiple sclerosis, which is characterized by CNS inflammation, oligodendrocyte loss, demyelination and axonal degeneration. Our studies have shown that oligodendrocytes respond to inflammation by activating the integrated stress response (ISR), which is a highly conserved, cytoprotective response that initiates with the phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2α). We have demonstrated using genetic models that oligodendrocytes with a diminished capacity to phosphorylate eIF2α in response to stress display increased susceptibility to inflammatory insults and that prolonging the phosphorylated state of eIF2α in oligodendrocytes increases their resistance to inflammation, both in vitro and in mouse models of inflammatory demyelination. This work has provided the foundation for an effort to protect oligodendrocytes from inflammation by pharmacologically enhancing the ISR. In contrast, recent reports indicate that that the inhibition of the ISR pathway provides protection in certain neurological disorders. Moreover, our unpublished work indicates that oligodendrocytes experiencing ER stress activate a distinct cytoprotective response from oligodendrocytes challenged by mediators of inflammation. The studies described in the current proposal are designed to uncover the molecular origin of this dichotomy. In aim 1 we will carry out a detailed characterization of the oligodendroglial stress response in Jimpy mutant mice, which represent a mouse model of the human leukodystrophy Pelizaeus- Merzbacher disease. Jimpy oligodendrocytes experience severe ER stress, and our preliminary data indicates that inhibiting ISR activation in these animals provides significant protection to oligodendrocytes. In aim 2 we will directly compare the various aspects of the response of oligodendrocytes experiencing ER stress with oligodendrocytes exposed to inflammation. Aims 3 and 4 will be devoted to an effort to determine if the activation of non-canonical cytoprotective responses explain the differential response of oligodendrocytes to ER stress and inflammation. In aim 3 will examine the contribution of NRF2, which is phosphorylated by the stress-sensing kinase PERK, to these responses. In aim 4 we will examine a recently discovered ER stress response pathway that is triggered by the cell migration inducing hyaluronidase 2 (TMEM2), which is of potential relevance to myelinating and remyelinating oligodendrocytes. Together the work described in this proposal will significantly advance our understanding of the response of oligodendrocytes to various cytotoxic insults, which will provide important information critical to the development of neuroprotective therapies for oligodendrocytes and other cells of the nervous system.


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 = $0 )
2025	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	24	5/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $546,443 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	24	1/10/2024	NON-COMPETING CONTINUATION	$507,009
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	24	8/5/2024	NON-COMPETING CONTINUATION	$0
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	24	4/25/2024	NON-COMPETING CONTINUATION	$39,434
														Subtotal = $546,443

Issue Date FY: 2023 ( Subtotal = $563,342 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	23	12/2/2022	NON-COMPETING CONTINUATION	$507,009
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	23	1/31/2023	NON-COMPETING CONTINUATION	$56,333
														Subtotal = $563,342

Issue Date FY: 2022 ( Subtotal = $563,342 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	22	12/21/2021	NON-COMPETING CONTINUATION	$507,010
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	22	3/31/2022	NON-COMPETING CONTINUATION	$56,332
														Subtotal = $563,342

Issue Date FY: 2021 ( Subtotal = $711,279 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	21	4/22/2021	COMPETING CONTINUATION	$152,631
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	1/28/2021	COMPETING CONTINUATION	$558,648
														Subtotal = $711,279

Issue Date FY: 2020 ( Subtotal = -$152,631 )
2020	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	6/22/2020	NON-COMPETING CONTINUATION	-$152,631
														Subtotal = -$152,631

Issue Date FY: 2019 ( Subtotal = $345,625 )
2019	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	1/28/2019	NON-COMPETING CONTINUATION	$345,625
														Subtotal = $345,625

Issue Date FY: 2018 ( Subtotal = $345,625 )
2018	2018	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	19	4/30/2018	NON-COMPETING CONTINUATION	$34,563
2018	2018	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	1/15/2018	NON-COMPETING CONTINUATION	$311,062
														Subtotal = $345,625

Issue Date FY: 2017 ( Subtotal = $345,625 )
2017	2017	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	18	7/13/2017	NON-COMPETING CONTINUATION	$34,563
2017	2017	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	1/20/2017	NON-COMPETING CONTINUATION	$311,062
														Subtotal = $345,625

Issue Date FY: 2016 ( Subtotal = $345,625 )
2016	2016	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	1/22/2016	NON-COMPETING CONTINUATION	$345,625
														Subtotal = $345,625

Issue Date FY: 2015 ( Subtotal = $345,625 )
2015	2015	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	1/15/2015	COMPETING CONTINUATION	$345,625
														Subtotal = $345,625

Issue Date FY: 2012 ( Subtotal = $330,138 )
2012	2012	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	6/14/2012	NON-COMPETING CONTINUATION	$330,138
														Subtotal = $330,138

Issue Date FY: 2011 ( Subtotal = $330,138 )
2011	2011	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	6/23/2011	NON-COMPETING CONTINUATION	$330,138
														Subtotal = $330,138

Issue Date FY: 2010 ( Subtotal = $333,507 )
2010	2010	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	6/9/2010	NON-COMPETING CONTINUATION	$333,507
														Subtotal = $333,507

Issue Date FY: 2009 ( Subtotal = $336,875 )
2009	2009	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	6/18/2009	NON-COMPETING CONTINUATION	$336,875
														Subtotal = $336,875

Issue Date FY: 2008 ( Subtotal = $336,875 )
2008	2008	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	6/30/2008	COMPETING CONTINUATION	$336,875
														Subtotal = $336,875

Issue Date FY: 2005 ( Subtotal = $340,759 )
2005	2005	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	4/18/2005	NON-COMPETING CONTINUATION	$340,759
														Subtotal = $340,759

Issue Date FY: 2004 ( Subtotal = $340,759 )
2004	2004	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	4/13/2004	NON-COMPETING CONTINUATION	$340,759
														Subtotal = $340,759

Issue Date FY: 2003 ( Subtotal = $340,759 )
2003	2003	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8		NON-COMPETING CONTINUATION	$340,759
														Subtotal = $340,759

Issue Date FY: 2002 ( Subtotal = $325,325 )
2002	2002	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Biological Basis Research in the Neurosciences	000	6	11/8/2001	NON-COMPETING CONTINUATION	$325,325
														Subtotal = $325,325

Issue Date FY: 2001 ( Subtotal = $321,969 )
2001	2001	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/15/2001	COMPETING CONTINUATION	$321,969
														Subtotal = $321,969

Issue Date FY: 2000 ( Subtotal = $221,326 ) (Continued on the next page)
Grand Total All Awards = $8,079,395

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Targeting the Integrated Stress Response to Protect Oligodendrocyte lineage Cells

Award Number: R01NS034939

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: 12/01/1996

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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