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Role of the myeloid mineralocorticoid receptor in vascular inflammation in atherosclerosis

Award Number: F30HL152505
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/16/2020
PERIOD OF PERFORMANCE END DATE: 05/15/2023

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Role of the myeloid mineralocorticoid receptor in vascular inflammation in atherosclerosis - PROJECT SUMMARY/ABSTRACT Despite advances in therapeutics and prevention, cardiovascular ischemic events remain the leading cause of death in the world. Activation of the mineralocorticoid receptor (MR) is associated with chronic inflammation of the blood vessel wall and formation of atherosclerotic plaques that lead to such ischemic events following their rupture and subsequent occlusion of blood flow to target organs. MR antagonists have been shown to reduce cardiovascular-related mortality in clinical trials as well as reduce plaque size and inflammation in atherosclerosis mouse models independently of changes in blood pressure. Previous studies have explored the contributions of MR in vascular cells to atherosclerosis. Deficiency of MR in endothelial cells but not smooth muscle cells attenuates atherosclerotic plaque inflammation, but neither reproduced changes in the proportion of pro- inflammatory myeloid cells in the plaque as seen with systemic MR blockade. MR in cells of the myeloid lineage (My-MR) has been shown to regulate pro-inflammatory gene expression in macrophages (MΦ) in vitro and contribute to plaque size in mouse models, but the mechanisms by which My-MR directly contributes to vascular inflammation in atherosclerosis are not known. We have demonstrated that the number of slow-rolling leukocytes in the mesenteric vasculature in response to TNFα decreases with My-MR deficiency. Additionally, the numbers of MΦ and T cells in atherosclerotic plaque decrease with My-MR deficiency. Therefore, we hypothesize that My-MR contributes to plaque inflammation by modulating myeloid cell recruitment to the vessel wall, MΦ polarization and proliferation, and MΦ interactions with effector T cells in the plaque in vivo. We have developed an atherosclerosis mouse model in which MR is specifically deleted in myeloid cells (and not in lymphocytes or any other vascular cells). In Aim 1, we will determine the role of My-MR in regulating MΦ recruitment to and proliferation within atherosclerotic plaques in vivo by intravital microscopy, flow cytometry, and histology. In Aim 2, we will explore the role of My-MR in regulating MΦ co-stimulatory molecule and cytokine signaling and therefore T cell function both in vivo and in vitro using flow cytometry, conditioned media, and co-culture experiments. Successful completion of these aims will elucidate My-MR-mediated pathways that regulate MΦ function and the overall plaque environment. These studies are expected to reveal potential immunotherapeutic targets for the prevention of cardiovascular disease. This proposal also includes a detailed training plan and integration of clinical training to prepare the PI for a career as an independent physician scientist.


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 = -$6,799 )
2024	2023	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	001	4	1/25/2024	NON-COMPETING CONTINUATION	-$6,799
2024	2022	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	002	3	3/22/2024	NON-COMPETING CONTINUATION	$0
2024	2022	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	000	3	1/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = -$6,799

Issue Date FY: 2023 ( Subtotal = $6,799 )
2023	2023	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	000	4	5/5/2023	NON-COMPETING CONTINUATION	$6,799
														Subtotal = $6,799

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	001	3	7/16/2022	NON-COMPETING CONTINUATION	$716
2022	2022	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	000	3	5/5/2022	NON-COMPETING CONTINUATION	$51,036
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $51,036 )
2021	2021	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	000	2	5/20/2021	NON-COMPETING CONTINUATION	$51,036
														Subtotal = $51,036

Issue Date FY: 2020 ( Subtotal = $41,270 )
2020	2020	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	001	1	5/11/2020	NEW	$0
2020	2020	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	5/11/2020	NEW	$41,270
														Subtotal = $41,270

Grand Total All Awards = $144,058

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Role of the myeloid mineralocorticoid receptor in vascular inflammation in atherosclerosis

Award Number: F30HL152505

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/16/2020

PERIOD OF PERFORMANCE END DATE: 05/15/2023

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