Mechanism of retinoic acid receptor induced innate immune responses

视黄酸受体诱导先天免疫反应的机制

• 批准号: 8120237
• 负责人: Philip T. Liu
• 金额: $ 10.8万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-04 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8120237
• 关键词: Address; Bacteria; California; Cells; Cholecalciferol; Clinical Research; Clinical Research Curriculum Award; Communicable Diseases; Complex; Data; Development; Disease; Endocrinology; Enzymes; Funding; Hormones; Host Defense; Host Defense Mechanism; Human; Immune response; Immune system; Immunity; Immunology; Inflammatory; Institutes; Interleukin-15; Laboratories; Ligands; Link; Los Angeles; Mediating; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Mission; Mixed Function Oxygenases; Molecular Immunology; Multi-Drug Resistance; Mycobacterium Infections; Mycobacterium tuberculosis; Pathway interactions; Play; Population; Predisposition; Public Health; Receptor Activation; Research; Research Personnel; Research Proposals; Resources; Retinoic Acid Receptor; Role; Signal Transduction; System; TLR2 gene; Testing; Toll-like receptors; Training; Tretinoin; Tuberculosis; Universities; Vitamin A; Vitamin A Deficiency; Vitamin D; Vitamin D2; Vitamin D3 Receptor; Work; Workload; antimicrobial; base; career development; combat; cytokine; design; functional outcomes; improved; in vivo; interest; knowledge base; macrophage; monocyte; pathogen; programs; prohormone; research study; resistant strain; response; therapeutic target

DESCRIPTION (provided by applicant): Previous studies have demonstrated that activation of the RAR results in antimicrobial activity against intracellular Mycobacterium tuberculosis. Our preliminary suggest that this antimicrobial activity could be mediated through activation of the vitamin D metabolic system. In addition our data indicate that concurrent TLR and RAR activation results in amplification of both macrophage differentiation and increase in the antimicrobial response. These data suggest an important role of RAR in the innate immune response and is suggestive of a potential mechanism by which vitamin A deficiency is correlated to increase susceptibility to disease in humans. The data generated from this study should provide new avenues of research into the host defense mechanisms against M. tuberculosis, as well as potential therapeutic targets. This application is submitted by Dr. Philip T. Liu, an investigator in the field of immunology whose objective is to transition into an independent researcher. As part of his career development, he will receive training in translational immunology and molecular endocrinology through co-mentorship by Dr. Robert L. Modlin and Dr. John S. Adams. Also, Dr. Genhong Cheng and Dr. Martin Hewison will provide additional mentorship in their respective fields of expertise. This proposal also outlines the course work through the K30 program at UCLA that will help Dr. Liu increase his knowledge base and improve his ability to execute translational clinical research. In the interim Dr. Liu will be provided research space and resources with Dr. Modlin's laboratory at the University of California at Los Angeles where Dr. Liu will have all the necessary resources to successfully complete his training. In summary, this application will serve not only to address immediate and long term scientific questions, but also the career development of Dr. Liu into a successful independent researcher. Relevance to Public Health: This research proposal is of interest to public health because it is designed to investigate how the human immune system combats tuberculosis, which currently ranks as the number one infectious disease in the world. Approximately one third of the world's population is infected, and recent increase in multidrug resistant strains of Mycobacterium tuberculosis, the causative agent of tuberculosis, has underscored the need for research into defense against the bacterium. By understanding the factors that regulate the immune response to this bacterium, we can design better therapies to treat this disease.

描述（由申请人提供）：先前的研究表明，RAR的激活导致针对细胞内分枝杆菌的抗菌活性。我们的初步表明，这种抗菌活性可以通过激活维生素D代谢系统来介导。此外，我们的数据表明，并发TLR和RAR激活会导致巨噬细胞分化和抗菌反应增加。这些数据表明RAR在先天免疫反应中的重要作用，并提示了一种潜在的机制，即维生素A缺乏症与人类对疾病的易感性相关。这项研究产生的数据应为针对结核分枝杆菌的宿主防御机制以及潜在的治疗靶标提供新的研究途径。该申请由免疫学领域的研究人员Philip T. Liu博士提交，其目的是过渡到独立的研究人员。作为他职业发展的一部分，他将通过Robert L. Modlin博士和John S. Adams博士的同学接受转化免疫学和分子内分泌学的培训。此外，Genhong Cheng博士和Martin Hewison博士将在各自的专业领域提供更多的指导。该提案还概述了UCLA的K30计划的课程工作，这将帮助Liu博士提高其知识库并提高他执行转化临床研究的能力。在临时，刘博士将与加利福尼亚大学洛杉矶分校的莫德林博士的实验室一起提供研究空间和资源，刘博士将拥有成功完成培训的所有必要资源。总而言之，该应用程序不仅可以解决直接和长期的科学问题，而且还将解决刘博士成为成功的独立研究人员的职业发展。 与公共卫生相关：该研究提案引起了公共卫生的关注，因为它旨在调查人类免疫系统如何打击结核病，该结核病目前是世界上排名第一的传染病。世界人口的大约三分之一被感染，最近的结核分枝杆菌多药抗性菌株的增加是结核病的致病药物，强调了对防御细菌的防御的需求。通过了解调节对该细菌免疫反应的因素，我们可以设计更好的治疗疗法来治疗该疾病。