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Development of Rac-Targeted Therapeutic Strategy for Treatment of Calcific Atherosclerosis

Award Number: R01HL139795
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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Development of Rac-Targeted Therapeutic Strategy for Treatment of Calcific Atherosclerosis - PROJECT SUMMARY/ABSTRACT: Coronary artery disease (CAD) from calcific atherosclerosis is the single leading cause of morbidity and mortality worldwide. The calcium composition of atherosclerotic plaque has predictive value in terms of cardiovascular events. Inflammation is likely a key mediator of vascular calcification, but immune signaling mechanisms that promote this process are minimally understood. Recently, the small GTPase, Rac2, was identified as a major inflammatory regulator of signaling that directs plaque osteogenesis. Atherosclerotic aortas from ApoE-/- mice fed a high fat diet supplemented with cholesterol demonstrated dynamic expression of Rac2 mRNA expression over time. Moreover, decreased Rac2 expression correlated with increased atherosclerotic calcification, both in the experimental animal model and in human coronary artery plaques. Rac2 -/-ApoE -/- mice helped to define a protective role of Rac2, which prevented progressive calcification through its suppression of Rac1-dependent macrophage IL-1β expression. Plaque and serum from mice with calcified plaque demonstrated increased expression of IL-1β, and moreover, treatment with the IL-1 receptor antagonist inhibited the enhanced atherosclerotic calcification. IL-1β expression was a key driver of vascular smooth muscle cell calcium deposition by its ability to promote osteogenic transcriptional programs, including expression of the osteogenic transcription factors, RUNX2, SOX9, OSX and MSX2. Bone marrow transplantation confirmed the progressive calcification of plaque attributable to Rac2 gene deletion was dependent on the hematopoietic compartment. Several key questions remain: 1) what is the role of macrophage Rac1 in plaque development and atherosclerotic calcification in standard experimental models; 2) are macrophages the key cellular source of plaque IL-1β; 3) how does Rac2 suppress Rac1-dependent macrophage IL-1β expression; and 4) are these signaling mechanisms relevant to calcified atherosclerotic plaque from patients with coronary artery disease? The overall objective of the proposed studies is to thoroughly answer these questions. Preliminary data demonstrate that Rac1 can be a key promoter of macrophage IL-1β expression and that Rac2 and Rac1 may antagonize each other through competition for a similar guanine nucleotide exchange factor, Tiam1, which is upregulated under conditions that activate IL-1β expression. The hypothesis is that macrophage Rac signaling determines atherosclerotic plaque IL-1β expression and consequent inflammatory atherosclerotic calcification, and thus disrupting this pathway can be an effective strategy for the prevention and treatment of CAD. Aim1 will define the role of macrophage Rac1 in plaque IL-1β expression and atherosclerotic calcification. Aim2 will confirm that Rac1 and Rac2 compete for Tiam1, a critical Rac-GEf that is upregulated during macrophage inflammatory activation as well as during experimental atherosclerosis, and that IL-1β expression and inflammatory atherosclerotic calcification are dependent on Tiam1 expression. Finally, Aim3 will confirm the validity of these macrophage signaling mechanisms in atherosclerotic plaque samples from patients with known coronary artery disease. Confirming that a macrophage Rac-IL-1β signaling axis is a central mechanism in inflammatory atherosclerotic calcification paves the way for developing a novel therapeutic strategy for treating coronary artery disease, as small molecular inhibitors of Rac1 and Rac1-Tiam1 interactions have been developed and are incorporated into a number of the proposed studies.


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 = -$25,352 )
2025	2022	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	000	5	11/27/2024	NON-COMPETING CONTINUATION	-$24,990
2025	2022	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	001	5	11/27/2024	SUPPLEMENT FOR EXPANSION	-$363
														Subtotal = -$25,352

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	000	5	1/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $322,589 )
2022	2022	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	000	5	11/26/2021	NON-COMPETING CONTINUATION	$286,178
2022	2022	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	001	5	12/3/2021	SUPPLEMENT FOR EXPANSION	$4,613
2022	2022	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	002	5	6/29/2022	NON-COMPETING CONTINUATION	$31,798
														Subtotal = $322,589

Issue Date FY: 2021 ( Subtotal = $376,738 )
2021	2021	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	000	4	11/17/2020	NON-COMPETING CONTINUATION	$339,062
2021	2021	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	001	4	5/27/2021	NON-COMPETING CONTINUATION	$37,676
														Subtotal = $376,738

Issue Date FY: 2020 ( Subtotal = $371,922 )
2020	2020	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	000	3	12/3/2019	NON-COMPETING CONTINUATION	$301,686
2020	2020	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	003	3	3/26/2020	SUPPLEMENT FOR EXPANSION	$0
2020	2020	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	002	3	3/7/2020	NON-COMPETING CONTINUATION	$15,879
2020	2020	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	001	3	1/15/2020	SUPPLEMENT FOR EXPANSION	$54,357
														Subtotal = $371,922

Issue Date FY: 2019 ( Subtotal = $354,093 )
2019	2019	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	000	2	12/15/2018	NON-COMPETING CONTINUATION	$376,891
2019	2019	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	001	2	5/21/2019	NON-COMPETING CONTINUATION	-$22,798
														Subtotal = $354,093

Issue Date FY: 2018 ( Subtotal = $333,245 )
2018	2018	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	000	1	1/9/2018	NEW	$323,024
2018	2018	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	001	1	9/12/2018	SUPPLEMENT FOR EXPANSION	$10,221
														Subtotal = $333,245

Grand Total All Awards = $1,733,235

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Development of Rac-Targeted Therapeutic Strategy for Treatment of Calcific Atherosclerosis

Award Number: R01HL139795

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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