Immunobiology of Corneal Antigen-Presenting Cells

角膜抗原呈递细胞的免疫生物学

• 批准号: 8292172
• 负责人: Pedram Hamrah
• 金额: $ 23.81万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292172
• 关键词: Address; Antigen-Presenting Cells; Antigens; Area; Autoimmune Process; Behavioral; Bone Marrow; Cell Communication; Cells; Characteristics; Cornea; Corneal Diseases; Critical Pathways; Dendritic Cells; Disease; Dry Eye Syndromes; Epithelial; Eye; Functional disorder; Goals; Graft Rejection; Grant; Hypersensitivity; Image; Immigration; Immune; Immune response; Immune system; Immunity; Immunobiology; Immunology; Immunotherapy; Infection; Inflammation; Inflammatory; Intervention; Keratitis; Keratoplasty; Kinetics; Langerhans cell; Lead; Left; Leukocyte Trafficking; Link; Location; Mentors; Modeling; Molecular; Molecular Target; Mus; Normal tissue morphology; Optics; Organ; Patients; Play; Population Heterogeneity; Positioning Attribute; Principal Investigator; Process; Property; Proteins; Regulatory T-Lymphocyte; Research; Research Institute; Research Personnel; Research Proposals; Resolution; Resources; Role; Scientist; Signal Transduction; Solid; Surface Antigens; Surveys; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Time; Tissues; Training; Transgenic Mice; Transplantation; Travel; Vision; Work; Wound Healing; adhesion receptor; career; cell mediated immune response; cell motility; experience; fMet-Leu-Phe receptor; immunogenic; immunopathology; immunoregulation; in vivo; innovation; insight; intravital microscopy; lymph nodes; macrophage; microbial; monocyte; movie; multi-photon; new therapeutic target; novel; programs; research study; response; skills; trafficking

Project Summary The overall goal of this proposal is to provide the principal investigator (PI) with the experiences and skills necessary to become an independent researcher, with the focus on studying immune cell trafficking mechanisms. My long-term career goal is to establish a comprehensive and independent research program dedicated to dissect the trafficking mechanism of immune cells in inflammatory and infectious corneal disease, leading to new therapeutic targets. Corneal antigen-presenting cells (APC) have a critical role in maintaining the clarity of the cornea and preserving vision. APC-mediated immune responses require contact-dependent information exchange between APC and T cells. Ag presentation by mature DC to naive T cells induces T cell activation and proliferation into effector T cells, which is in turn thought to be controlled by several mechanisms, including the action of regulatory T cells (Treg). Career decisions taken by APC are regulated molecules on the surface of APC and T cells. Despite their unique position in the immune system, the signals APC need to enter the cornea, and the clues they require to leave the cornea, are still largely unexplored. In preliminary work for this project, we have developed a new multiphoton intravital microscopy (MP-IVM) model to study APC in intact corneas of anesthetized mice. This imaging approach uses transgenic mice, in which APC subsets expresses distinct genetically encoded fluorescent tags, and produces 3D time-lapse movies of APC at subcellular resolution, interacting with surrounding cells. These cells will be studied to investigate the traffic signals that guide them to normal and inflamed corneas and will be used to address the following three specific aims: 1.) To dissect the molecular mechanisms by which APC travel to normal and inflamed corneas; 2.) To analyze the mechanisms involved in migration of APC from the cornea to local lymph nodes under normal conditions and during inflammation; and 3) examine the spatial, temporal and behavioral characteristics of donor and host APC after corneal transplantation and their interaction with T cells in lymph nodes. This aim will also analyze how effector T cells or Tregs enter the cornea. The proposed experiments will generate a comprehensive, mechanism-oriented survey of the behavioral similarities and differences between distinct APC subsets under normal condition and inflammation.

项目概要 该提案的总体目标是为首席研究员（PI）提供经验和技能 成为一名独立研究人员所必需的，重点是研究免疫细胞贩运 机制。我的长期职业目标是建立一个全面且独立的研究计划 致力于剖析炎症和感染性角膜疾病中免疫细胞的运输机制， 导致新的治疗靶点。角膜抗原呈递细胞（APC）在 保持角膜的清晰度并保护视力。 APC 介导的免疫反应 需要 APC 和 T 细胞之间的接触依赖性信息交换。 Ag 演示者 成熟的 DC 转化为初始 T 细胞，诱导 T 细胞活化并增殖为效应 T 细胞，这是在 人们认为它是由多种机制控制的，包括调节性 T 细胞 (Treg) 的作用。 APC做出的职业决定是APC和T细胞表面的调节分子。尽管 它们在免疫系统中的独特地位、APC 进入角膜所需的信号以及线索 它们需要离开角膜，但很大程度上仍未被探索。在这个项目的前期工作中，我们 开发了一种新的多光子活体显微镜 (MP-IVM) 模型来研究完整的 APC 麻醉小鼠的角膜。这种成像方法使用转基因小鼠，其中 APC 亚群 表达独特的基因编码荧光标签，并以 APC 的速度制作 3D 延时电影 亚细胞分辨率，与周围细胞相互作用。将研究这些细胞以调查 引导他们到达正常角膜和发炎角膜的交通信号，并将用于解决以下问题 三个具体目标：1.) 剖析 APC 恢复正常和发炎的分子机制 角膜； 2.) 分析APC从角膜迁移至局部淋巴的机制 正常情况下和炎症期间的淋巴结； 3）检查空间、时间和 角膜移植后供体和宿主APC的行为特征及其相互作用 淋巴结中含有 T 细胞。该目标还将分析效应 T 细胞或 Tregs 如何进入角膜。 拟议的实验将产生一个全面的、以机制为导向的调查 正常条件下不同 APC 亚群之间的行为异同 炎。