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Revealing novel pathogenic and repairing mechanisms of CADASIL disease.

Award Number: R56NS116232
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: 07/15/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Revealing novel pathogenic and repairing mechanisms of CADASIL disease. - PROJECT SUMMARY/ABSTRACT Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) represents the most common form of hereditary ischemic stroke (microinfarcts) and vascular dementia. CADASIL is a monogenic cerebral small vessel disease driven by progressive degeneration of mural cells due to NOTCH3 gene mutation in the mural cells (vascular smooth muscle cells and pericytes). This vascular degeneration-induced dementia is one of the diseases sharing a similar pathological mechanism of “Vascular Contributions to Cognitive Impairment and Dementia” (VCID). The NIH has designated VCID as a critical research area requiring studies to explore new molecular mechanisms of cerebrovascular pathology and potential treatments for vascular dementia. CADASIL mainly affects young and middle-aged adults and causes severe disability and early death. No treatment is available to stop or delay disease progression for CADASIL. Although the causative role of NOTCH3 gene mutation in CADASIL was revealed in 1996, it still remains unclear today how NOTCH3 mutation drives cerebrovascular defects. The lack of this pathogenic knowledge creates a critical barrier for the development of therapeutic strategies for CADASIL. Our earlier studies have demonstrated that combined treatment of two hematopoietic growth factors, stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) ameliorates vascular smooth muscle cell degeneration, cerebrovascular regression, capillary thrombosis, microinfarcts, blood-brain barrier (BBB) leakage, and cognitive impairments in a mouse model of CADASIL (TgNotch3R90C mice). It remains to be determined, however, how the SCF+G-CSF treatment enhances cerebrovascular repair in TgNotch3R90C mice. The objective of this application is to determine a novel pathogenic mechanism for CADASIL and the underlying mechanism for SCF+G-CSF-enhanced cerebrovascular repair in TgNotch3R90C mice. Using 2- photon cortical capillary circulation imaging, BBB integrity assay, pharmacological intervention, and Cre-Lox technology, this application will define how impaired cerebral capillary circulation in TgNotch3R90C mice is improved by SCF+G-CSF treatment (Aim 1), how cerebral capillary leakage in TgNotch3R90C mice is ameliorated by SCF+G-CSF treatment (Aim 2), and how mural cell-produced pathogenic molecules drive progressive cerebrovascular defects and how SCF+G-CSF treatment ameliorates the cerebrovascular defects by modulating the pathogenic molecules (Aim 3) in TgNotch3R90C mice. It is expected that the findings of this mechanistic study will significantly advance the understanding of the pathogenesis for CADASIL and will reveal new targets and new routes to develop novel treatments for CADASIL. This proposed study fits within the research priorities of NIH-highlighted VCID research.


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 = -$264 )
2025	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/13/2024	NEW	-$264
														Subtotal = -$264

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/4/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $495,169 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/7/2021	NEW	$495,169
														Subtotal = $495,169

Grand Total All Awards = $494,905

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Revealing novel pathogenic and repairing mechanisms of CADASIL disease.

Award Number: R56NS116232

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: 07/15/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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