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Impact of SARS-Cov-2 on a Rat Model Cerebral Amyloid Angiopathy

Award Number: R21AG089374
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Impact of SARS-Cov-2 on a Rat Model Cerebral Amyloid Angiopathy - Although the pandemic phase of SARS-CoV-2 infections has diminished the disease remains highly endemic in the US population with current weekly hospitalizations from infection remaining in the thousands and significant morbidity. Further, there is always the risk that new SARS-CoV-2 variants may arise that are more transmissible and/or pathogenic. Therefore, SARS-CoV-2 infections will remain a significant health issue in the US for the foreseeable future. Although SARS-CoV-2 infection is largely viewed as a respiratory disease there is substantial evidence that SARS-2-CoV-2 infection is a “vascular disease” caused by endothelial cell uptake of the virus via angiotensin converting enzyme 2 (ACE2) that can affect various organs including the brain. With regards to the cerebral vasculature, SARS-CoV-2 infection can cause coagulopathy and local thrombotic events in the brain including ischemic and hemorrhagic stroke. How other cerebral vascular diseases interact with SARS-CoV-2 infections is poorly understood. Cerebral amyloid angiopathy (CAA) is a common amyloidal form of cerebral small vessel disease of the elderly that is characterized by the accumulation of fibrillar amyloid b-protein (Ab) in blood vessels of the brain. CAA is also a frequent vascular comorbidity in patients with Alzheimer’s disease and related disorders (ADRD). Cerebral vascular accumulation of Aβ can result in perivascular neuroinflammation, cerebral infarction, microbleeds and intracerebral hemorrhages. Because of these cerebral vascular insults, CAA is a significant cause of vascular-mediated cognitive impairment and dementia (VCID). Recently, we generated a novel transgenic rat model for CAA, designated rTg-D, that recapitulates many of the pathological features of the disease in humans including cortical and meningeal vascular amyloid, cerebral microbleeds, small vessel occlusions, and VCID. The rTg-D rat model provides a useful platform for investigating the pathogenesis of CAA and the impact of comorbidities. There are reports in the literature indicating that SARS-CoV-2 infection can impact CAA in a highly detrimental manner promoting hemorrhagic events. Yet despite this link the effects of SARS-CoV-2 infection on the course of pathology of CAA and other ADRDs remains largely unknown. Thus, the goal of this R21 exploratory proposal is to investigate the impact of SARS-CoV-2 infection on the emergence, progression and severity of CAA in the novel rTg-D transgenic rat model of CAA. To accomplish this goal, we propose two specific aims. First, we will determine if the SARS-CoV-2 spike 1 protein accelerates the emergence and progression CAA and associated pathologies in younger rTg-D rats. Second, we will determine if the SARS-CoV-2 spike 1 protein exacerbates CAA associated vasculopathies in aged rTg-D rats. Our studies will combine quantitative pathological measures and transcriptomic approaches in a novel preclinical model of CAA to identify key elements of activation pathways that are shared between CAA and SARS-CoV-2 infection.


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 = $236,250 )
2025	2025	UNIVERSITY OF RHODE ISLAND	75 LOWER COLLEGE RD RM 103	KINGSTON	RI	02881	WASHINGTON	USA	Aging Research	000	2	6/18/2025	NON-COMPETING CONTINUATION	$236,250
														Subtotal = $236,250

Issue Date FY: 2024 ( Subtotal = $196,875 )
2024	2024	UNIVERSITY OF RHODE ISLAND	75 LOWER COLLEGE RD RM 103	KINGSTON	RI	02881	WASHINGTON	USA	Aging Research	000	1	9/10/2024	NEW	$196,875
														Subtotal = $196,875

Grand Total All Awards = $433,125

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Impact of SARS-Cov-2 on a Rat Model Cerebral Amyloid Angiopathy

Award Number: R21AG089374

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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