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Endothelial cell dysfunction in cerebral aneurysm pathogenesis

Award Number: R01NS111119
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: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Endothelial cell dysfunction in cerebral aneurysm pathogenesis - Project Summary/Abstract: Endothelial dysfunction is highlighted as an early marker of vascular abnormality preceding cerebral aneurysm formation, but the molecular events behind this transformation remain unclear. Inflammatory cytokines including interleukin-2 (IL-2) mediate vascular disease, but its role in cerebral aneurysm pathophysiology is unknown. Our preliminary data indicate that IL-2 is expressed in human cerebral aneurysm tissue and induces a phenotypic switch in endothelial cell (EC) function from the maintenance of vasomotor activity, to promotion of inflammation and matrix remodeling. We have also found that inhibition of the IL-2 target protein mTOR with rapamycin reduced aneurysm progression and rupture in a mouse cerebral aneurysm model. Collectively this preliminary data suggests a vital role of the IL-2/mTOR pathway in aneurysm progression. The objective of this grant is to characterize the role of IL-2 activated mTOR in EC dysfunction and aneurysm development and progression. The central hypothesis of this proposal is that IL-2/mTOR inhibition promotes repopulation of EC and decreases inflammation, which halts aneurysm progression and promotes vascular healing. In this proposal, we will determine the role of IL-2 activated mTOR in aneurysm formation, progression, and rupture and define the mechanisms by which IL-2/mTOR promotes EC dysfunction (Aim 1). We will treat experimental aneurysms with a novel stent delivering controlled release of the IL-2/mTOR inhibitor rapamycin to determine if IL-2/mTOR inhibition reverses EC dysfunction while decreasing inflammation (Aim 2). Finally, we will determine IL-2 expression, mTOR activation and EC dysfunction in human cerebral aneurysmal tissue and intra-aneurysmal blood and if rapamycin treatment prior to surgery reduces IL-2/mTOR signaling and EC dysfunction (Aim 3). The proposed research is innovative in that successful completion of this project will determine the events behind EC dysfunction which lead to aneurysm progression and will help develop novel minimally invasive therapeutic strategies for aneurysm obliteration.


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: 2024 ( Subtotal = $497,786 )
2024	2024	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/13/2023	NON-COMPETING CONTINUATION	$461,864
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/17/2024	NON-COMPETING CONTINUATION	$35,922
														Subtotal = $497,786

Issue Date FY: 2023 ( Subtotal = $509,382 )
2023	2023	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/19/2022	NON-COMPETING CONTINUATION	$458,445
2023	2023	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	2/2/2023	NON-COMPETING CONTINUATION	$50,937
														Subtotal = $509,382

Issue Date FY: 2022 ( Subtotal = $497,351 )
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/18/2021	NON-COMPETING CONTINUATION	$447,615
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/12/2022	NON-COMPETING CONTINUATION	$49,736
														Subtotal = $497,351

Issue Date FY: 2021 ( Subtotal = $489,752 )
2021	2021	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/11/2021	NON-COMPETING CONTINUATION	$48,976
2021	2021	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/25/2020	NON-COMPETING CONTINUATION	$440,776
														Subtotal = $489,752

Issue Date FY: 2020 ( Subtotal = $425,613 )
2020	2020	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/25/2019	NEW	$425,613
														Subtotal = $425,613

Grand Total All Awards = $2,419,884

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Endothelial cell dysfunction in cerebral aneurysm pathogenesis

Award Number: R01NS111119

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: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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