Role of ABCA7 in iNKT development and function and its impact on atherosclerosis

ABCA7 在 iNKT 发育和功能中的作用及其对动脉粥样硬化的影响

基本信息

批准号：
8893134
负责人：
Heba Nowyhed
金额：
$ 2.85万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2016-01-26
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8893134
关键词：
ATP-Binding Cassette Transporters Adenosine Triphosphate Adoptive Transfer Adult American Antigen-Presenting Cells Antigens Arterial Fatty Streak Arteriosclerosis Atherosclerosis Binding Biology Blood Vessels Bone Marrow Cardiovascular Diseases Categories Cell physiology Cells Chimera organism Cholesterol Confocal Microscopy Coronary heart disease Data Development Diet Dose Generations Health Heart Diseases Host Defense Hydroxymethylglutaryl-CoA Reductase Inhibitors ITGAX gene Immune Immune system In Vitro Individual Inflammation Journals Knock-out Learning Lipids Literature Measures Mediating Mus Natural Immunity North America Pathogenesis Peripheral Phagocytosis Pharmaceutical Preparations Pharmacology Physiology Play Population Process Regulation Role Surface System T-Cell Activation T-Cell Development T-Cell Receptor T-Lymphocyte Testing Therapeutic Thrombosis Thymus Gland Transgenic Mice adaptive immunity apolipoprotein E-3 Leiden atorvastatin extracellular in vivo killer T cell meetings response thymocyte trafficking

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular disease is the single largest killer of adults in North America with current therapeutics against atherosclerosis represented by drugs known as statins. Invariant Natural Killer T (iNKT) cells, T lymphocytes with qualities characterized by both innate and adaptive immune responses, have been demonstrated as key players in the progression of atherosclerosis. ABCA7, an adenosine triphosphate binding cassette transporter, has been shown to be upregulated in immune cells in response to statins. Studies have shown direct involvement of statin treatment in the regulation of the host defense system through the modulation of ABCA7. The beneficial effects of statins in atherosclerosis have been partly attributed to their immunomodulating functions. We propose that statins act on ABCA7 expression in iNKT cells, and that this alteration in ABCA7 brings about developmental and functional aberrancies in the iNKT population, which has a direct effect on the development/progression of atherosclerosis. We will first examine in detail the role ABCA7 plays in iNKT cell function and development as we have preliminary data that suggests the absence of ABCA7 negatively impacts iNKT development and function. Our first specific aim will test the hypothesis that ABCA7 modulates CD1d function in thymocytes altering the thymic developmental progression of iNKT cells. We will examine the functional capabilities of ABCA7 knockout DP thymocytes in vitro, and in vivo through the generation of mixed bone marrow chimeras. We will utilize the mixed bone marrow chimeras to also test the role of ABCA7 on iNKT in a cell intrinsic effect. The second specific aim will test the hypothesis that ABCA7 modulates CD1d function in peripheral antigen presenting cells, impacting iNKT activation. This will be done through the use of confocal microscopy where we will analyze CD1d localization and lipid antigen trafficking in ABCA7 knockout CD11c+ cells. Specific aim three will test whether statin administration causes ABCA7-mediated changes in iNKT cell function ultimately effecting the development of atherosclerosis. We will perform adoptive transfers of ABCA7.ldlr double knockout and ldlr knockout iNKT cells, with or without statin treatment prior to transfer, into ldlr.Jalpha18 double knockout recipients for atherosclerosis studies.

描述（由申请人提供）：心血管疾病是北美最大的成年人杀手，目前针对动脉粥样硬化的治疗剂以他汀类药物为代表。不变的天然杀手T（INKT）细胞，具有先天和适应性免疫反应特征的特征性的T淋巴细胞，已被证明是动脉粥样硬化进展的关键参与者。 ABCA7是一种三磷酸腺苷结合盒转运蛋白，已显示在免疫细胞中响应他汀类药物而被上调。研究表明，通过调节ABCA7，他汀类药物治疗直接参与了宿主防御系统的调节。他汀类药物在动脉粥样硬化中的有益作用部分归因于其免疫调节功能。我们建议他汀类药物对inkt细胞中的ABCA7表达作用，并且ABCA7中的这种改变会带来inkt种群中的发育和功能差，这对动脉粥样硬化的发育/进展有直接影响。我们将首先详细研究ABCA7在Inkt细胞功能和开发中的作用，因为我们拥有初步数据，这表明缺乏ABCA7会对Inkt的发展和功能产生负面影响。我们的第一个具体目的将检验以下假设：ABCA7在胸腺细胞中调节CD1D功能，以改变inkt细胞的胸腺发育进展。我们将通过混合骨髓嵌合体在体外检查ABCA7基因敲除DP胸腺细胞的功能能力，并在体内检查。我们将利用混合的骨髓嵌合体来测试ABCA7在inkt固有效果中的作用。第二个特定目的将检验以下假设：ABCA7在外周抗原呈递细胞中调节CD1D功能，从而影响inkt激活。这将通过使用共聚焦显微镜完成，我们将在ABCA7基因敲除CD11C+细胞中分析CD1D定位和脂质抗原运输。特定目标三将测试他汀类药物的给药是否导致ABCA7介导的Inkt细胞功能的变化最终会影响动脉粥样硬化的发展。我们将进行ABCA7.LDLR双基因敲除和LDLR敲除Inkt细胞的收养转移，并在转移之前进行他汀类药物治疗，以进行LDLR.JALPHA18双敲除敲除接受者进行动脉粥样硬化研究。