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Mechanistic and Functional Evaluation of a Model of Cerebral Small Vessel Disease

Award Number: R01NS140370
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: 05/01/2025
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Mechanistic and Functional Evaluation of a Model of Cerebral Small Vessel Disease - PROJECT SUMMARY Vascular contributions to cognitive impairment and dementia (VCID) describes any level of cognitive alteration attributable to cerebrovascular pathologies. After Alzheimer disease, VCID is the second leading cause of dementia and accounts for ~15-30% of all dementia cases. Cerebral small vessel disease (cSVD) accounts for up to 20% of all strokes and is the most common pathology underlying VCID. Importantly, the pathogenesis of cSVD is poorly understood which represents a major barrier for developing therapies. COL4A1 and COL4A2 mutations cause multisystem disorder for which cSVD disease is the major consequence. Cerebrovascular disease in individuals with COL4A1 or COL4A2 mutations have hallmarks of cSVD – subcortical microbleeds, enlarged perivascular spaces, and lacunar infarcts and Col4a1+/Mut mice faithfully model patient phenotypes. Moreover, Col4a1+/Mut mice have age-related cerebrovascular dysfunction including loss of myogenic tone and impaired hyperemic responses that are thought to be critical to VCID progression. Importantly, strong genetic evidence indicates that COL4A1 and COL4A2 contribute to general cerebrovascular health and idiopathic cSVD suggesting that understand pathogenic mechanisms contributing this form of monogenic cSVD may also provide important insight into idiopathic cSVD and VCID. We discovered that TGFβ signaling is elevated in Col4a1+/Mut mice, genetically decreasing TGFβ signaling ameliorates cSVD severity in mice, and that acutely inhibiting TGFβ signaling restores myogenic tone to ex vivo cerebral arteries from Col4a1 mutant mice. Here, we seek to understand the molecular mechanisms by which collagen IV a1a1a2(IV) regulates TGFβ signaling. We will also use mouse models to perform intravital imaging of the cerebral vasculature and cerebral hemodynamics, evaluate behavioral assays of cognitive impairment, and test hypothesis that dysregulation of matrix metalloproteinases contribute to pathogenesis. The successful completion of this project could provide significantly greater understanding of idiopathic cSVD and establish clinically relevant in vivo outcomes for testing future disease modifying therapies for an important monogenetic form of cSVD.


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 = $792,523 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/18/2026	NON-COMPETING CONTINUATION	$792,523
														Subtotal = $792,523

Issue Date FY: 2025 ( Subtotal = $770,502 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/1/2025	NEW	$770,502
														Subtotal = $770,502

Grand Total All Awards = $1,563,025

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Mechanistic and Functional Evaluation of a Model of Cerebral Small Vessel Disease

Award Number: R01NS140370

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: 05/01/2025

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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