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Novel Knock in Mutation Rat Model for CARASIL

Award Number: R21AG075024
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Novel Knock in Mutation Rat Model for CARASIL - Cerebral small vessel diseases (CSVD) are a major cause of vascular cognitive impairment and dementia (VCID) in the elderly, account for a significant number of ischemic and hemorrhagic strokes and are present in Alzheimer’s disease and related disorders (ADRD). CSVDs broadly fall into two classes: 1) amyloidal CVSD including sporadic and familial forms of cerebral amyloid angiopathy (CAA) and ADRD and 2) non-amyloidal CSVD involving common conditions such as hypertension, diabetes, arteriolosclerosis and a number of rare monogenic hereditary forms that includes cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which is a rare autosomal recessive, inherited non-hypertensive CSVD that presents with early adult-onset VCID, gait disturbances, alopecia and spondylosis. Magnetic resonance imaging (MRI) studies of CARASIL patients show pronounced white matter (WM) changes including multiple lacunar infarcts, extensive WM lesions predominantly involving basal ganglia and brain stem and, in some cases, subcortical cerebral microbleeds. The WM lesions appear to result from small vessel damage characterized by extensive loss of cerebral arterial smooth muscle cells, loss of mural extracellular matrix and thickening and fragmentation of the internal elastic lamina. Although monogenic forms of CSVD are rare they share many clinical and neuropathological features with more common sporadic CSVDs including white matter damage, cerebral infarcts, cerebral bleeds and VCID. Previous studies have revealed that CARASIL results from specific mutations in the highly conserved high temperature requirement serine proteinase A1 (htra1) gene that markedly reduce or abolish the serine proteinase activity of Htra1 protein and believed to cause disruption of normal TGFb signaling that leads to smooth muscle degeneration and other cerebral arteriopathies in CARASIL patients. Mechanistic studies of CARASIL are hindered by the lack of effective animal models that faithfully recapitulate pathological features of human disease. Accordingly, the overall aim of this exploratory proposal is to generate and characterize a novel rat model of CARASIL by introducing a specific CARASIL mutation (R302Q) in the endogenous rat htra1 gene that will eliminate serine proteinase activity. To accomplish this overall goal, we propose the following three sets of experiments: First, we will conduct molecular and pathological characterization of a novel mutant ‘knock in’ rat model for CARASIL. Second, we will determine the consequences of emerging CSVD pathology on advanced cognitive and motor functions in the novel CARASIL rats. Lastly, we will perform neuroimaging studies to determine the impact of emerging CSVD on brain pathology as defined by MRI in the novel CARASIL rats. Successful completion of this work will provide a novel and unique animal model to the field of CSVD to more fully understand how this condition contributes to cerebral arteriopathy, WM damage and VCID. Further, it will provide a novel platform to investigate therapeutic strategies to target these pathologies in VCID and ADRD.


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 = -$2 )
2026	2022	UNIVERSITY OF RHODE ISLAND	75 LOWER COLLEGE RD RM 103	KINGSTON	RI	02881	WASHINGTON	USA	Aging Research	000	1	1/7/2026	NEW	-$2
														Subtotal = -$2

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF RHODE ISLAND	75 LOWER COLLEGE RD RM 103	KINGSTON	RI	02881	WASHINGTON	USA	Aging Research	000	1	8/2/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $443,069 )
2022	2022	UNIVERSITY OF RHODE ISLAND	75 LOWER COLLEGE	KINGSTON	RI	02881	WASHINGTON	USA	Aging Research	000	1	7/25/2022	NEW	$443,069
														Subtotal = $443,069

Grand Total All Awards = $443,067

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Novel Knock in Mutation Rat Model for CARASIL

Award Number: R21AG075024

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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