The role of ABCG1 in Atherosclerosis Progression and TH17 Differentiation

ABCG1 在动脉粥样硬化进展和 TH17 分化中的作用

• 批准号: 8205386
• 负责人: LaTeira Denise Haynes
• 金额: $ 3.28万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8205386
• 关键词: 7-ketocholesterol; ATP-Binding Cassette Transporters; Antiatherogenic; Antibodies; Aorta; Apolipoprotein E; Arterial Fatty Streak; Arteries; Atherogenic Diet; Atherosclerosis; Autoimmunity; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cause of Death; Cell Differentiation process; Cell physiology; Cells; Cholesterol; Chronic; Data; Development; Diet; Disease; Dose; Flow Cytometry; Generations; Hematopoietic; High Density Lipoproteins; Immune; Immune system; In Vitro; Inflammation; Interferons; Interleukin-17; Interleukin-4; Ligands; Lipids; Lymphocyte; Measures; Mus; Nuclear Receptors; Peripheral; Plant Roots; Play; Production; Progressive Disease; Regulatory T-Lymphocyte; Reporting; Role; Severities; Spleen; Stimulus; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Western World; atherogenesis; atheroprotective; chromatin immunoprecipitation; feeding; lipid metabolism; prevent; response; reverse cholesterol transport; therapeutic target

DESCRIPTION (provided by applicant): Atherosclerosis is the major cause of cardiovascular disease, which is the leading cause of death in the western world. Atherosclerotic plaques are found in the arterial wall and consist of lipids and immune cells. T lymphocytes have been shown to play an active role in atherosclerosis. Regulatory T cells (Tregs) are a subset of T cells that express FoxP3 and suppress autoimmunity. Tregs have been reported to be antiatherogenic. TH17 cells are a subset of T cells that express ROR3t and secrete IL-17 that are implicated in promoting autoimmunity but their role in atherosclerosis is controversial. Tregs and Th17 cells have an intimate developmental relationship and Tregs have been shown to be able to convert to TH17 cells with the appropriate stimuli. ABCG1 is an ATP-binding cassette transporter that participates in reverse cholesterol transport by transferring excess cholesterol from peripheral cells to HDL. Mice that lack ABCG1 in hematopoietic cells are protected from developing severe atherosclerosis. The mechanism that confers this atheroprotection is currently unknown. We have preliminary data that there is increased ROR3t expression in Tregs from ApoE-/- mice fed an atherogenic diet; however ROR3T expression is not increased in ApoE-/- ABCG1-/- mice fed the same diet. ROR3t is the master regulator of TH17 cells and an increase in its expression may indicate a shift from antiatherogenic Tregs to TH17 cells during early atherogenesis. We also have data that there is a marked reduction in IL-17 production by T cells in ApoE-/-ABCG1-/- mice fed western diet. We hypothesize that absence of ABCG1 in CD4 T cells is atheroprotective due to impaired TH17 differentiation. This proposal will study the role of ABCG1 on CD4+ T cell function during atherosclerosis progression in the following specific aims. Specific Aim 1 will test the hypothesis that absence of ABCG1 in CD4+ T cells inhibits TH17 differentiation. We have preliminary data showing that ABCG1 deficiency greatly reduces the differentiation of TH17 cells. We will investigate the mechanisms involved in this phenomenon. Specific Aim 2 will test the hypothesis that absence of ABCG1 in CD4+ T cells is atheroprotective. We will produce a CD4+ T cell specific deletion of ABCG1 in atherosclerosis prone mice by crossing ABCG1fl/flApoE-/- mice with CD4-Cre mice. These mice will be put on an atherogenic diet for 8 or 20 weeks to investigate early and advanced atherosclerosis respectively. Atherosclerosis severity will then be measured. The numbers of TH1, TH2, Tregs and TH17 cells present in the aortic walls and spleens of the mice during atherosclerosis progression using flow cytometry. The role of ABCG1 in CD4+ T cells, particularly it's role in Tregs and TH17 cells, may be important in promoting atherosclerosis progression. This study may clarify the currently controversial roles of ABCG1 and TH17 cells in atherosclerosis and help determine their potential as therapeutic targets of this disease. PUBLIC HEALTH RELEVANCE: Atherosclerosis is the major cause of cardiovascular disease, which is the leading cause of death in the western world. My proposal investigates how cholesterol modulates immune cell function in atherosclerosis progression.

描述(申请人提供)：动脉粥样硬化是心血管疾病的主要原因，在西方世界，这是导致死亡的主要原因。动脉粥样硬化斑块位于动脉壁内，由脂质和免疫细胞组成。T淋巴细胞已被证明在动脉粥样硬化中起着积极的作用。调节性T细胞(Tregs)是表达FoxP3并抑制自身免疫的T细胞亚群。据报道，Tregs具有抗动脉粥样硬化的作用。Th17细胞是T细胞的一个亚群，表达ROR3t并分泌IL-17，与促进自身免疫有关，但它们在动脉粥样硬化中的作用存在争议。Tregs和Th17细胞具有密切的发育关系，并且Tregs被证明能够在适当的刺激下转化为TH17细胞。Abcg1是一种三磷酸腺苷结合盒转运体，通过将多余的胆固醇从外周细胞转移到高密度脂蛋白，参与胆固醇的反向转运。在造血细胞中缺乏Abcg1的小鼠可以免受严重动脉粥样硬化的影响。赋予这种动脉粥样硬化保护的机制目前尚不清楚。我们有初步数据表明，在喂食致动脉粥样硬化饲料的ApoE-/-小鼠的Tregs中，ROR3t的表达增加；然而，在喂食相同食物的ApoE-/-Abcg1-/-小鼠中，ROR3T的表达并没有增加。ROR3t是TH17细胞的主要调节因子，其表达的增加可能表明在动脉粥样硬化形成早期从抗动脉粥样硬化的Tregs向TH17细胞的转变。我们也有数据表明，在喂食西方饮食的ApoE-/-Abcg1-/-小鼠中，T细胞产生的IL-17显著减少。我们假设，由于TH17分化受损，CD4T细胞中缺少Abcg1是一种动脉粥样硬化保护作用。本研究将在以下特定目标下研究Abcg1在动脉粥样硬化进展过程中对CD4+T细胞功能的影响。特定目标1将检验这一假设，即CD4+T细胞中缺少Abcg1会抑制TH17的分化。我们的初步数据显示，Abcg1缺乏会极大地降低TH17细胞的分化。我们将调查这一现象涉及的机制。特定目标2将检验这一假设，即在CD4+T细胞中缺乏Abcg1具有动脉粥样硬化保护作用。我们将通过将ABCG1fl/flApoE-/-小鼠与CD4-CRE小鼠杂交，在易患动脉粥样硬化的小鼠中产生CD4+T细胞特异性的Abcg1缺失。这些小鼠将接受8周或20周的致动脉粥样硬化饮食，以分别研究早期和晚期的动脉粥样硬化。然后将测量动脉粥样硬化的严重程度。用流式细胞术检测动脉粥样硬化进展过程中TH1、TH2、Tregs和TH17细胞在小鼠主动脉壁和脾中的数量。Abcg1在CD4+T细胞中的作用，特别是在Tregs和TH17细胞中的作用，可能在促进动脉粥样硬化的进展中起重要作用。这项研究可能会阐明目前有争议的Abcg1和TH17细胞在动脉粥样硬化中的作用，并有助于确定它们作为这种疾病的治疗靶点的潜力。 公共卫生相关性：动脉粥样硬化是心血管疾病的主要原因，在西方世界，这是导致死亡的主要原因。我的建议是研究胆固醇如何在动脉粥样硬化进展中调节免疫细胞功能。