Wednesday, January 15, 2025 1/15/2025

Na/H Exchanger in Microglial Metabolism and Function

Award Number: R01NS048216
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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PROJECT SUMMARY This is our revised competitive renewal application (R01 NS048216-16 A1, 02-04-2005 to 01-28-2021), “Na/H exchanger in microglial metabolism and function”. In this renewal proposal, we will study Na+/H+ exchanger isoform 1 (NHE1) in regulating microglial immunometabolism and cellular function in brain tissue repair. Microglial phagocytosis is important for debris clearance, remyelination, and synapse remodeling for tissue repair in neurodegenerative diseases [stroke, vascular dementia, Alzheimer’s Disease (AD), ADRD, etc.]. Therefore, modulating microglial phagocytosis functions presents a novel therapeutic strategy for neurodegenerative diseases. However, to date, the mechanisms that govern coordinated regulation of microglial energy metabolism and phagocytosis are not completely understood, filling this knowledge gap is the central scientific premise for our study. We reported previously that NHE1 protein-mediated H+ efflux (in exchange of Na+ influx) alkalinizes intracellular pH (pHi) in microglia, which promotes sustained NADPH oxidase (NOX2) activation because the latter is inhibited by low pHi. We obtained the following new findings: 1). selective deletion of microglial Nhe1 in the Cx3cr1-CreER+/- ;Nhe1f/f (cKO) mice reduced pro-inflammatory microglial responses but increased their restorative transformation after ischemic stroke; 2). Nhe1 cKO microglia exhibited increased oxidative phosphorylation (OXPHOS), post- stroke phagocytosis and spine stripping activities; 3). bulk RNAseq transcriptome analysis showed that the cKO microglia displayed significantly elevated genes encoding key rate-limiting enzymes for OXPHOS, the hallmark LXR/RXR-APOE-TREM2 pathway genes for phagocytosis and cholesterol efflux, and genes for phagolysosomal function; 4). the cKO stroke mice concurrently exhibited enhanced oligodendrogenesis and remyelination with improved cognitive functions. These findings strongly suggest that microglial NHE1 activity is involved in regulating microglial immunometabolism and functions in post-stroke brains and emerges as a novel therapeutic target. We will test our hypothesis by investigating: 1) the impact of selective deletion of microglial Nhe1 in cKO mice on phagocytosis transcriptomic and functional changes in post-stroke brains; 2) how Nhe1 cKO microglia enhance phagocytosis and cholesterol efflux for remyelination in post-stroke brains; 3) how Nhe1 cKO microglia boost mitochondrial biogenesis and OXPHOS to support cellular functions in post-stroke brains. Impact, completion of this study will improve our understanding on coordinated regulation of immunometabolism and cellular functions in microglia; and will shed light on NHE1 protein as a therapeutic target for promoting restorative microglial metabolism and functions for brain tissue repair in 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 = $385,621 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	7/19/2024	NON-COMPETING CONTINUATION	$385,621
														Subtotal = $385,621

Issue Date FY: 2023 ( Subtotal = $397,548 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	17	9/14/2023	NON-COMPETING CONTINUATION	$397,548
2023	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	16	6/15/2023	COMPETING CONTINUATION	$5,346
2023	2020	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	6/15/2023	NON-COMPETING CONTINUATION	-$5,346
														Subtotal = $397,548

Issue Date FY: 2022 ( Subtotal = $396,585 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	16	8/10/2022	COMPETING CONTINUATION	$397,548
2022	2020	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	8/4/2022	NON-COMPETING CONTINUATION	-$963
														Subtotal = $396,585

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	5/21/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $342,344 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	3/4/2020	NON-COMPETING CONTINUATION	$342,344
														Subtotal = $342,344

Issue Date FY: 2019 ( Subtotal = $342,344 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	7/18/2019	NON-COMPETING CONTINUATION	$342,344
														Subtotal = $342,344

Issue Date FY: 2018 ( Subtotal = $341,614 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	1/24/2018	NON-COMPETING CONTINUATION	$307,452
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	13	5/15/2018	NON-COMPETING CONTINUATION	$34,162
														Subtotal = $341,614

Issue Date FY: 2017 ( Subtotal = $339,062 )
2017	2017	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	12	6/26/2017	NON-COMPETING CONTINUATION	$33,907
2017	2017	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	2/1/2017	NON-COMPETING CONTINUATION	$305,155
														Subtotal = $339,062

Issue Date FY: 2016 ( Subtotal = $336,875 )
2016	2016	UNIVERSITY OF PITTSBURGH	FIFTH & BIGELOW BOULEVARD	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	2/17/2016	COMPETING CONTINUATION	$336,875
2016	2013	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	2/15/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $336,875

Issue Date FY: 2015 ( Subtotal = $0 )
2015	2013	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	4/3/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $329,553 )
2013	2013	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	5/24/2013	NON-COMPETING CONTINUATION	$22,197
2013	2013	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	4/23/2013	NON-COMPETING CONTINUATION	$307,356
														Subtotal = $329,553

Issue Date FY: 2012 ( Subtotal = $341,507 )
2012	2012	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	5/16/2012	NON-COMPETING CONTINUATION	$341,507
														Subtotal = $341,507

Issue Date FY: 2011 ( Subtotal = $318,991 )
2011	2011	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	7	9/13/2011	NON-COMPETING CONTINUATION	-$167,930
2011	2011	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	6/10/2011	NON-COMPETING CONTINUATION	$26,040
2011	2011	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	8	9/13/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$167,930
2011	2011	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	4/11/2011	NON-COMPETING CONTINUATION	$292,951
														Subtotal = $318,991

Issue Date FY: 2010 ( Subtotal = $322,246 )
2010	2010	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	4/26/2010	NON-COMPETING CONTINUATION	$322,246
														Subtotal = $322,246

Issue Date FY: 2009 ( Subtotal = $337,626 )
2009	2009	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	5/6/2009	COMPETING CONTINUATION	$337,626
2009	2008	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/6/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $337,626

Issue Date FY: 2008 ( Subtotal = $185,976 )
2008	2008	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/18/2007	NON-COMPETING CONTINUATION	$185,976
														Subtotal = $185,976

Issue Date FY: 2007 ( Subtotal = $186,133 )
2007	2007	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/23/2007	NON-COMPETING CONTINUATION	$186,133
														Subtotal = $186,133

Issue Date FY: 2006 ( Subtotal = $191,870 )
2006	2006	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/2/2006	NON-COMPETING CONTINUATION	$191,870
														Subtotal = $191,870

Issue Date FY: 2005 ( Subtotal = $196,646 )
2005	2005	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/4/2005	NEW	$196,646
														Subtotal = $196,646

Grand Total All Awards = $5,292,541

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Na/H Exchanger in Microglial Metabolism and Function

Award Number: R01NS048216

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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