# Novel Knock in Mutation Rat Model for CARASIL

> **NIH NIH R21** · UNIVERSITY OF RHODE ISLAND · 2022 · $443,069

## Abstract

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 ar...

## Key facts

- **NIH application ID:** 10518554
- **Project number:** 1R21AG075024-01A1
- **Recipient organization:** UNIVERSITY OF RHODE ISLAND
- **Principal Investigator:** Helene D Benveniste
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $443,069
- **Award type:** 1
- **Project period:** 2022-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10518554

## Citation

> US National Institutes of Health, RePORTER application 10518554, Novel Knock in Mutation Rat Model for CARASIL (1R21AG075024-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10518554. Licensed CC0.

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