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: 8308740
• 负责人: LaTeira Denise Haynes
• 金额: $ 3.32万
• 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/8308740
• 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.

描述（由申请人提供）：动脉粥样硬化是心血管疾病的主要原因，心血管疾病是西方世界的主要死亡原因。动脉粥样硬化斑块位于动脉壁中，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发挥积极作用。调节性T细胞（Tcells）是表达FoxP 3并抑制自身免疫的T细胞亚群。据报道，睾酮具有抗动脉粥样硬化作用。TH 17细胞是表达ROR 3 t并分泌IL-17的T细胞亚群，其参与促进自身免疫，但其在动脉粥样硬化中的作用是有争议的。Th 17细胞和Tcl 3细胞具有密切的发育关系，并且Tcl 3细胞已被证明能够在适当的刺激下转化为Th 17细胞。ABCG 1是一种ATP结合盒转运蛋白，通过将多余的胆固醇从外周细胞转移到HDL来参与胆固醇的逆向转运。在造血细胞中缺乏ABCG 1的小鼠被保护免于发展严重的动脉粥样硬化。赋予这种动脉粥样硬化保护作用的机制目前尚不清楚。我们有初步的数据表明，在喂食致动脉粥样硬化饮食的ApoE-/-小鼠的Tcells中，ROR 3 t表达增加;然而，在喂食相同饮食的ApoE-/-ABCG 1-/-小鼠中，ROR 3 T表达没有增加。ROR 3 t是TH 17细胞的主要调节因子，其表达的增加可能表明在早期动脉粥样硬化形成过程中从抗动脉粥样硬化的TCR 3细胞向TH 17细胞的转变。我们也有数据表明，在喂食西方饮食的ApoE-/-ABCG 1-/-小鼠中，T细胞产生的IL-17显著减少。我们假设CD 4 T细胞中ABCG 1的缺失是由于受损的TH 17分化所致的动脉粥样硬化保护作用。本研究旨在探讨ABCG 1在动脉粥样硬化进展过程中对CD 4 + T细胞功能的作用。具体目标1将检验CD 4 + T细胞中ABCG 1的缺乏抑制TH 17分化的假设。我们有初步的数据表明，ABCG 1缺陷大大降低了TH 17细胞的分化。我们将研究这种现象的机制。特异性目的2将检验CD 4 + T细胞中ABCG 1缺失具有动脉粥样硬化保护作用的假设。我们将通过将ABCG 1fl/flApoE-/-小鼠与CD 4-Cre小鼠杂交，在动脉粥样硬化易感小鼠中产生ABCG 1的CD 4 + T细胞特异性缺失。这些小鼠将接受致动脉粥样硬化饮食8周或20周，以分别研究早期和晚期动脉粥样硬化。然后测量动脉粥样硬化严重程度。采用流式细胞术检测动脉粥样硬化进展过程中小鼠主动脉壁和脾脏中存在的TH 1、TH 2、TH 17和TH 17细胞的数量。ABCG 1在CD 4 + T细胞中的作用，特别是它在T细胞和TH 17细胞中的作用，可能在促进动脉粥样硬化进展中是重要的。这项研究可能会澄清目前有争议的作用ABCG 1和TH 17细胞在动脉粥样硬化，并帮助确定其作为这种疾病的治疗靶点的潜力。