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"Novel roles of the TRPC3 channel in macrophage functions: implications in atherosclerosis"

“TRPC3 通道在巨噬细胞功能中的新作用：对动脉粥样硬化的影响”

基本信息

批准号：
9336433
负责人：
Guillermo Vazquez
金额：
$ 37.88万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9336433
关键词：
Affect Anti-Inflammatory Agents Anti-inflammatory ApoE knockout mouse Apoptosis Apoptotic Arterial Fatty Streak Atherosclerosis Backcrossings Bone Marrow CCL19 gene CCL2 gene Carotid Artery Diseases Cells Cellularity Characteristics Chemotactic Factors Clinical Control Animal Coronary artery Cues Disease Elements Event Exhibits Genes Genetic Goals Health Human Pathology In Vitro Incidence Inflammation Inflammatory Knock-out Lasers Lead Lesion Link Mediator of activation protein MicroRNAs Molecular Morbidity - disease rate Mus NTN1 gene Necrosis Phenotype Process Publishing RNA Repression Research Resistance Role Rupture Signal Transduction Societies Stenosis Stress Symptoms Time United States Up-Regulation Western Blotting Work chemokine receptor drug development gain of function genetic manipulation improved in vivo innovation loss of function macrophage migration mimetics mortality mouse model new therapeutic target novel phenotypic biomarker receptor response transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is the main cause of coronary and carotid artery disease and a leading cause of morbidity/mortality in the United States. Ischemic symptoms due to advanced stenosis or thromboembolic events that follow plaque rupture are major clinical manifestations of the disease. Efforts in the field are aimed at reducing plaque progression, improve stability of advanced plaques or stimulate plaque regression. The particular impact that macrophage apoptosis and migration have in advanced lesions is subject of intensive research efforts. Yet, their potential applicability to human pathology is still under debate. Definitions can be achieved by acknowledging the distinctive impact of macrophage diversity in plaque composition and fate, and by exploring molecular components that may selectively affect a macrophage type and not others. The long term goal of this proposal is to examine the contribution of macrophage Transient Receptor Potential Canonical 3 (TRPC3) to these mechanisms in the context of atherosclerosis. In recent work we showed that advanced plaques in ApoE knockout mice with bone marrow deletion of TRPC3 have less necrosis and macrophage apoptosis than controls, and bone marrow derived macrophages from mice with macrophage-specific deletion of TRPC3 (MacTRPC3KO) and differentiated in vitro to the M1 type, have reduced ER stress-induced apoptosis. Remarkably, M2 macrophages were not affected. Our preliminary studies in MacTRPC3KOApoEKO mice show that, compared to controls, advanced plaques have reduced macrophage content and that TRPC3 deletion promotes a reduction in M1/M2 ratios, and decreased apoptosis. We have also found that TRPC3 deficient M1, but not M2 macrophages, have augmented in vitro migration. The general hypothesis is that by virtue of its roles in mechanisms associated to apoptosis and migration of M1 macrophages TRPC3 can exert profound effects on the characteristics of plaque composition and integrity. It is anticipated that suppression of macrophage TRPC3 in vivo will lessen cellularity and necrosis of advanced plaques and favor regressive conditions. In specific aim 1 we will examine the impact of TRPC3 expression and constitutive function on inflammatory signaling and migration of polarized macrophages under conditions of ER stress. In specific aim 2 we will study the impact of macrophage-specific loss or gain of TRPC3 function on the characteristics of atherosclerotic lesions in a mouse model of the disease. In specific aim 3 we will examine the impact of macrophage-specific loss or gain of TRPC3 function on macrophage migration and plaque regression in mouse models of the disease.