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Astrocytic WNK-SPAK-NKCC1 Cascade in White Matter Astrogliosis and Injury

Award Number: R01NS119166
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: 04/15/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Astrocytic WNK-SPAK-NKCC1 Cascade in White Matter Astrogliosis and Injury - PROJECT SUMMARY Vascular contributions to cognitive impairment and dementia (VCID) are currently considered as one of the leading causes of dementing illness. The key feature of VCID is diffuse white mater lesions (WML) and hippocampal damage, including myelin loss, axonal disruption, and astrogliosis. However, the underlying molecular and cellular mechanisms for WML, hippocampal damage, and cognitive impairment are not well understood. Hypertension and atherosclerosis are the most significant risk factors for dementia epidemics. Using two mouse models of VCID with chronic bilateral carotid artery stenosis (BCAS), we detected progressive activation of the WNK-SPAK-NKCC1 protein complex in white matter tracts and hippocampus, which is associated with brain lesion and cognitive deficits. Brain Na+-K+-Cl- cotransporter isoform 1 (NKCC1) contributes to intracellular Na+ and Cl- overload, cytotoxic edema, and excitotoxic ischemic neuronal damage. The serine- threonine WNK kinase family [with no lysine (K)], and its downstream kinase SPAK (the STE20/SPS1-related proline/alanine-rich kinase) activate NKCC1 activity via protein phosphorylation. In our pilot study, we detected that BCAS triggered a time-dependent activation of the SPAK-NKCC1 protein complex, specifically in corpus collosum (CC) and hippocampal GFAP+ reactive astrocytes. How the WNK-SPAK-NKCC1 protein complex is stimulated and its role in the pathogenesis of BCAS-induced WML and hippocampal lesion remains unknown. We detected BCAS-induced elevation of interleukin-18 receptor 1 (IL-18R1) expression and nuclear translocation of pNF-κB in GFAP+ reactive astrocytes, which are correlated with increased NF-kB recruitment on the Wnk/Spak/Nkcc1 gene promoters. Importantly, blocking SPAK function with a novel, selective SPAK inhibitor ZT-1a significantly reduced WML, hippocampal CA1 region neurodegeneration, and attenuated cognitive function impairment. Therefore, we propose that activation of the WNK-SPAK-NKCC1 complex plays an important role in the BCAS-induced pathogenesis. We hypothesize that (1) BCAS-induced hypoperfusion stimulates the IL-18/IL-18R-MyD88-NF-κB cascade to upregulate the WNK-SPAK-NKCC1 complex in reactive astrocytes; (2) elevated astrocytic WNK-SPAK-NKCC1 signaling and astrogliosis contribute to cell death of oligodendrocytes (OLs), demyelination, CA1 neuronal loss, and cognitive deficits; and (3) Post-BCAS administration of the novel SPAK kinase inhibitor ZT-1a reduces brain lesions and cognitive deficits by attenuating astrogliosis and degeneration of OLs and CA1 neurons. These hypotheses will be tested in the following specific aims: Aim 1. Identify molecular mechanisms that stimulate WNK-SPAK-NKCC1 cascade activation and astrogliosis in white matter tracts and hippocampus after BCAS. Aim 2. Determine causative roles of BCAS-induced astrocytic WNK-SPAK-NKCC1 cascade activation in brain lesion and cognitive function impairment. Aim 3. Investigate the efficacy of the novel SPAK inhibitor ZT-1a in reducing astrogliosis, brain lesion, and cognitive function impairment in the BCAS mice.


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: 2026 ( Subtotal = $450,735 )
2026	2026	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	3/27/2026	NON-COMPETING CONTINUATION	$450,735
														Subtotal = $450,735

Issue Date FY: 2025 ( Subtotal = $470,365 )
2025	2025	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	4/9/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$470,365
2025	2024	THE UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	5/9/2025	NON-COMPETING CONTINUATION	$0
2025	2024	THE UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/9/2025	NON-COMPETING CONTINUATION	$0
2025	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	000	1	1/10/2025	NEW	$0
														Subtotal = $470,365

Issue Date FY: 2024 ( Subtotal = $455,568 )
2024	2024	THE UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/7/2024	NON-COMPETING CONTINUATION	$410,012
2024	2024	THE UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	7/11/2024	NON-COMPETING CONTINUATION	$45,556
														Subtotal = $455,568

Issue Date FY: 2023 ( Subtotal = $458,632 )
2023	2023	UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	3/20/2023	NON-COMPETING CONTINUATION	$458,632
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	000	1	12/15/2022	NEW	-$435,363
2023	2022	UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	12/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$435,363
														Subtotal = $458,632

Issue Date FY: 2022 ( Subtotal = $510,233 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/13/2022	NEW	$510,233
														Subtotal = $510,233

Grand Total All Awards = $2,345,533

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Astrocytic WNK-SPAK-NKCC1 Cascade in White Matter Astrogliosis and Injury

Award Number: R01NS119166

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: 04/15/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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