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Targeting Kruppel-like Transcription Factor for White and Grey Matter Protection in Vascular Cognitive Impairment and Dementia

Award Number: R01NS131122
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: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Targeting Kruppel-like Transcription Factor for White and Grey Matter Protection in Vascular Cognitive Impairment and Dementia - Vascular cognitive impairment and dementia (VCID), a type of cognitive disorder mainly induced by cerebrovascular pathology and dysfunction, is widely recognized as the second most common cause of dementia after Alzheimer’s disease, and results in tremendous economic and social burdens on our society. Despite recent progress in VCID research, our understanding of cerebrovascular contributions to the pathogenesis of VCID is still limited, and the effective therapeutic approaches for VCID are unavailable. Krüppel-like factors (KLFs) are members of the zinc finger family of transcription factors and consist of 18 members that have been shown to play key roles in cellular growth and differentiation. Cumulative studies have documented that several KLFs (KLF2, KLF4, KLF5, KLF6, KLF8, KLF11, KLF13, KLF14, and KLF15) are implicated in developmental and pathological vascular processes. It is becoming apparent that KLFs are also implicated in regulating the pathogenesis of cerebrovascular diseases and warrant further investigation. KLF11 is a unique diabetes-associated KLF transcription factor among 18 KLF family members and is highly expressed in vascular endothelium. We reported for the first time that KLF11 functions as an important mediator in acute stroke-induced brain injury. However, the function and mechanisms of KLF11 in regulating cerebrovascular pathogenesis and progression of cognitive decline are totally unknown in VCID. In our recent preliminary studies, we have shown that KLF11 expression is significantly decreased in the mouse cerebral vasculature after VCID. Of note, EC-selective KLF11 transgenic overexpression displays reduced cognitive impairments in the experimental VCID mouse model, whereas KLF11 genetic deficiency results in increased cognitive impairments, white matter injury and neuronal loss. Mechanistically, we have documented that KLF11 genetic deficiency increased BBB permeability in mice after VCID. We further found several KLF11 binding sites in the promoter region of major endothelial tight junctions, and genetic deletion of KLF11 in VCID mice significantly reduced cerebral expression of claudin-5. These findings have provided the basis for our Central Hypothesis that vascular KLF11 attenuates BBB disruption and subsequent pathological cascades after chronic cerebral hypoperfusion, thereby contributing to increased BBB stabilization, reduced white matter/neuronal loss, and improved long-term cognitive outcomes in VCID. Three specific aims will be performed in this proposal. Aim 1: Define the role of vascular KLF11 in long-term cognitive disorders, brain white matter injury, and neuronal loss in experimental VCID; Aim 2: Elucidate the mechanisms of vascular KLF11-mediated brain protection in VCID; Aim 3: Explore systematic delivery of TAT- KLF11 protein as a potential therapy in VCID. Elucidating KLF11 cerebrovascular protection may help us to discover vascular contribution to brain white and grey matter injury and dementia, and lead us to develop novel and effective treatment against VCID.


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 = $580,783 )
2026	2026	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	4	5/11/2026	NON-COMPETING CONTINUATION	$580,783
														Subtotal = $580,783

Issue Date FY: 2025 ( Subtotal = $97,344 )
2025	2025	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	3	6/12/2025	NON-COMPETING CONTINUATION	$97,344
														Subtotal = $97,344

Issue Date FY: 2024 ( Subtotal = $609,466 )
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	002	2	7/22/2024	NON-COMPETING CONTINUATION	$0
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	2	4/15/2024	NON-COMPETING CONTINUATION	$609,466
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	001	2	6/28/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $609,466

Issue Date FY: 2023 ( Subtotal = $609,466 )
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	000	1	6/22/2023	NEW	$609,466
														Subtotal = $609,466

Grand Total All Awards = $1,897,059

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Targeting Kruppel-like Transcription Factor for White and Grey Matter Protection in Vascular Cognitive Impairment and Dementia

Award Number: R01NS131122

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: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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