"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”

• 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
• 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

 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.

 描述（由申请人提供）：动脉粥样硬化是冠状动脉和颈动脉疾病的主要原因，也是美国发病率/死亡率的主要原因。由于斑块破裂后的晚期狭窄或血栓栓塞事件引起的缺血症状是该疾病的主要临床表现。本领域的努力旨在减少斑块进展，改善晚期斑块的稳定性或刺激斑块消退。巨噬细胞凋亡和迁移在晚期病变中的特殊影响是深入研究的主题。然而，它们对人类病理学的潜在适用性仍在研究之中。 辩论通过确认巨噬细胞多样性对斑块组成和命运的独特影响，以及通过探索可能选择性影响巨噬细胞类型而不是其他类型的分子组分，可以实现定义。本提案的长期目标是研究巨噬细胞瞬时受体电位规范3（TRPC 3）在动脉粥样硬化背景下对这些机制的贡献。在最近的研究中，我们发现骨髓TRPC 3缺失的ApoE敲除小鼠中的晚期斑块比对照组具有更少的坏死和巨噬细胞凋亡，并且来自巨噬细胞特异性TRPC 3缺失（MacTRPC 3 KO）并在体外分化为M1型的小鼠的骨髓衍生的巨噬细胞具有减少的ER应激诱导的凋亡。值得注意的是，M2巨噬细胞没有受到影响。我们在MacTRPC 3 KOApoEKO小鼠中的初步研究表明，与对照组相比，晚期斑块减少了巨噬细胞含量，TRPC 3缺失促进了M1/M2比值的降低和细胞凋亡的减少。我们还发现，TRPC 3缺陷型M1，而不是M2巨噬细胞，增强了体外迁移。一般的假设是，凭借其在与M1巨噬细胞的凋亡和迁移相关的机制中的作用，TRPC 3可以对斑块组成和完整性的特征产生深远的影响。预期体内巨噬细胞TRPC 3的抑制将减少晚期斑块的细胞构成和坏死，并有利于消退性病症。在具体目标1中，我们将研究TRPC 3表达和组成性功能对ER应激条件下极化巨噬细胞的炎症信号传导和迁移的影响。在具体目标2中，我们将研究巨噬细胞特异性TRPC 3功能的丧失或获得对该疾病小鼠模型中动脉粥样硬化病变特征的影响。在具体目标3中，我们将检查TRPC 3功能的巨噬细胞特异性丧失或获得对疾病小鼠模型中巨噬细胞迁移和斑块消退的影响。