Role of ABCG1 in lipid homeostasis, inflammation and innate immunity

ABCG1 在脂质稳态、炎症和先天免疫中的作用

基本信息

批准号：
8486177
负责人：
Elizabeth Joanna Tarling
金额：
$ 9.05万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2013-08-21 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8486177
关键词：
ATP-Binding Cassette Transporters Adoptive Transfer Affect Alveolar Macrophages Antibodies Antigens Apolipoprotein E Apoptosis Area Arterial Fatty Streak Arteries Atherosclerosis Attenuated Autoimmunity B-Lymphocytes Biological Models Biology Bone Marrow Transplantation California Cardiovascular Diseases Cells Cellular biology Characteristics Cholesterol Cholesterol Esters Cholesterol Homeostasis Chronic Clinical Complex Data Deposition Development Disease Disease Progression Exhibits Foam Cells Frequencies Generations Goals Greater sac of peritoneum Homeostasis Human Immune response Immune system In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Intervention Intracellular Transport Lesion Lipids Lipoidosis Los Angeles Lung Lymphocyte Malignant Neoplasms Mediating Mediator of activation protein Mentors Metabolic Diseases Metabolism Molecular Movement Mus Natural Immunity Nuclear Receptors Obesity Pleural cavity Postdoctoral Fellow Proteins Public Health Publishing Relative (related person)Research Personnel Role Scientist Signal Transduction Site Spleen Sterols System Testing Tissues Training Translating Universities Vascular System Wild Type Mouse Work alveolar lamellar body alveolar type II cell atheroprotective career development cell type cytokine disease characteristic disorder prevention extracellular insight interest lipid metabolism loss of function macrophage macrophage scavenger receptors monocyte novel oxidation oxidized lipid oxidized low density lipoprotein pathogen post-doctoral training programs response sterol homeostasis surfactant

项目摘要

DESCRIPTION (provided by applicant): This application details a five-year career development program to facilitate the transition from a mentored post-doctoral fellow to an independent researcher. The applicant has completed 4.5 years of post- doctoral training, 1 in the UK and 3.5 at the University of California, Los Angeles. The applicant will continue to be mentored by Dr Peter Edwards, a recognized leader in the field of cholesterol and lipid metabolism. Dr Peter Tontonoz, a highly respected scientist with expertise in the areas of nuclear receptors, inflammation and cardiovascular disease, will act as co-mentor to the applicant. Importantly, Drs Edwards and Tontonoz have successfully trained a number of investigators who have become independent academic scientists. Continued active interactions with Drs Kenneth Dorshkind (UCLA) and Joe Witztum (UCSD), both experts in B-1 B cells and natural antibodies (NAbs), adds particular strengths to specific aspects of the application. Inflammation is a hallmark characteristic of diseases such as atherosclerosis, autoimmunity, obesity and cancer. Inflammation is a stereotypical response of the innate (inborn) immune system to pathogens. Factors that influence inflammation can have a profound effect on disease progression. For example, the formation of fatty streaks and subsequent progression to atherosclerotic lesions is associated with accumulation of cholesterol and cholesterol esters within the intima of the artery wall. These changes in intracellular and extracellular lipids resul in an inflammatory response that is generally thought to have deleterious effects on lesion development. I am particularly interested in identifying proteins that affect lipid deposition, inflammation and disease, and then defining their mechanism of action. To this end, we have shown that i) the ATP Binding Cassette Transporter G1 (ABCG1) modulates both intracellular sterol movement and facilitates the transport of cellular cholesterol and oxysterols to exogenous lipid acceptors and ii) mice lacking ABCG1 develop severe pulmonary lipidosis and chronic inflammation. Unexpectedly, Abcg1-/- mice exhibit reduced atherosclerosis, despite enhanced levels of pro-inflammatory cytokines and increased pulmonary lipid deposition. The primary aim of this proposal is to understand the mechanisms involved in maintaining inflammatory responses and the role of ABCG1 in lipid homeostasis, inflammation, and innate immunity. In Specific Aim 1 I will test the hypothesis that cell-specific deletion of ABCG1 has significant consequences for inflammatory responses. I propose to generate mice deficient in ABCG1 specifically in type II pneumocytes (T2 cells; Abcg1T2-/T2-). I will then study the Abcg1T2-/T2- mie to determine the specific importance of T2 cell ABCG1 on surfactant metabolism, lung lipid homeostasis, including the effect on the generation of lipid antigens that affect innate immunity and inflammation. In Specific Aim 2 I will test the hypothesis that loss of ABCG1 modulates innate immunity, inflammation and atherosclerosis progression. Using adoptive transfer studies and Rag2-/-Ldlr-/- hyperlipidemic mice, I will then determine the relative contribution of differen B cell subtypes that lack ABCG1 on the development of atherosclerosis, focusing particularly on the athero- protective function of B-1 B cells and secreted NAbs. One of the long term goals of the studies put forward in this application is to further understand factors that mediate inflammatory responses and how they translate to disease prevention, using the innate immune system and atherosclerosis as model systems.

描述（由申请人提供）：此申请详细介绍了一项为期五年的职业发展计划，以促进从受过指导的博士后研究员到独立研究人员的过渡。申请人已经完成了4。5年的博士后培训，在英国进行了1项，在洛杉矶分校完成了3.5年。申请人将继续由胆固醇和脂质代谢领域的公认领导者彼得·爱德华兹（Peter Edwards）博士进行指导。彼得·顿托兹（Peter Tontonoz）博士是一位在核受体，炎症和心血管疾病领域具有专业知识的高度尊敬的科学家，他将担任申请人的同事。重要的是，爱德华兹博士和Tontonoz博士成功地培训了许多已成为独立学术科学家的调查人员。与B-1 B细胞和天然抗体（NABS）的专家（NABS）持续与Kenneth Dorshkind博士（UCLA）和Joe Witztum（UCSD）持续积极相互作用，为应用程序的特定方面增添了特殊的优势。炎症是诸如动脉粥样硬化，自身免疫性，肥胖和癌症等疾病的标志性特征。炎症是先天性（先天性）免疫系统对病原体的刻板印象。影响炎症的因素可能会对疾病进展产生深远的影响。例如，脂肪条纹的形成以及随后向动脉粥样硬化病变的进展与动脉壁内膜内胆固醇和胆固醇酯的积累有关。细胞内和细胞外脂质在炎症反应中恢复的这些变化，通常认为对病变的发育产生有害影响。我对鉴定影响脂质沉积，炎症和疾病，然后定义其作用机理的蛋白质特别感兴趣。为此，我们表明i）i）ATP结合盒转运蛋白G1（ABCG1）调节细胞内固醇运动，并促进细胞胆固醇和氧替酚的运输，而氧化脂蛋白酚和氧甲醇对外源性脂质受体以及II）缺乏ABCG1的小鼠，缺乏ABCG1的炎性炎症和慢性脂肪症。。出乎意料的是，尽管促炎细胞因子水平增强并增加了肺脂质沉积，但ABCG1 - / - 小鼠表现出降低的动脉粥样硬化。该提案的主要目的是了解维持炎症反应和ABCG1在脂质稳态，炎症和先天免疫中所涉及的机制。在特定目标1中，我将检验以下假设：ABCG1的细胞特异性缺失对炎症反应有重大影响。我建议在II型肺核细胞（T2细胞; ABCG1T2-/T2-）中特别生成缺乏ABCG1的小鼠。然后，我将研究ABCG1T2-/T2- MIE，以确定T2细胞ABCG1对表面活性剂代谢，肺脂质稳态的特定重要性，包括对影响先天免疫和炎症的脂质抗原产生的影响。在特定目标2中，我将检验以下假设：ABCG1的丧失调节先天免疫，炎症和动脉粥样硬化的进展。然后，我将使用rag2 - / - ldlr - / - 高脂小鼠，然后我将确定缺乏ABCG1对动脉粥样硬化发展的不同B细胞亚型的相对贡献细胞和分泌的NAB。该应用中提出的研究的长期目标之一是进一步了解介导炎症反应以及它们如何使用先天免疫系统和动脉粥样硬化作为模型系统的因素。