TAM Receptor Regulation of Innate Immunity

TAM 受体对先天免疫的调节

基本信息

批准号：
7994189
负责人：
Greg E Lemke
金额：
$ 46.92万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7994189
关键词：
Actins Address Adult Agonist Alleles Antigen-Presenting Cells Apoptotic Autoimmune Diseases Autoimmunity B-Cell Activation B-Lymphocytes Bacteria Binding Biochemical Biological Cell Culture Techniques Cell membrane Cell physiology Cells Chronic Cultured Cells Cytoskeleton Defect Dendritic Cells Dendritic cell activation Development Dimerization Disease Exposure to Eye Family Feedback Functional disorder Gases Genes Genetic Goals Health Homo Human Immune Immune response Immune system In Vitro Infection Inflammation Inflammatory Inflammatory Response Intervention Invaded Knock-out Knockout Mice Ligands Lupus Lymphatic Diseases Mediating Methods Molecular Mus Mutant Strains Mice Natural Immunity Natural Killer Cells Normal Cell Normal tissue morphology Pathway interactions Phagocytosis Phenotype Play Process Production Protein S Proteins Reagent Receptor Activation Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Relative (related person)Rheumatoid Arthritis Role STAT1 gene Sepsis Series Signal Pathway Signal Transduction Sjogren&apos s Syndrome Structure Structure of retinal pigment epithelium System Systemic Lupus Erythematosus T-Lymphocyte TNF gene To autoantigen Toll-like receptors Virus base cytokine design embryonic stem cell extracellular homologous recombination immune function inhibitor/antagonist insight macrophage member mutant novel pathogen receptor recombinase research study therapeutic target transcription factor

项目摘要

The experiments of this application are designed to elucidate the roles that the TAM receptor tyrosine kinases - Tyro 3, Axl, and Mer - play in the homeostatic regulation of innate immunity. We have discovered that these receptors, together with their agonists Gas 6 and Protein S, are essential intrinsic inhibitors of the inflammatory response to infection. Tyro 3, Axl, and Mer are expressed by macrophages and dendritic cells (DCs). These cells respond to invading bacteria and viruses by producing a panolpy of pro-inflammatory and inflammatory cytokines, which, while essential to the defeat of pathogens, are also injurious to normal cells and tissues. If unchecked at the end of the innate immune response, production of cytokines such as TNF-a leads to chronic inflammatory disease and autoimmunity. The proposed studies exploit a powerful set of genetic reagents - mutant mice that lack the function of each of the receptors and of the activating ligands. As adults, these mice display devastating immune deficits, including lymphoproliferation marked by severe splenomegalogy and lymphadenopathy, systemic hyperactivation of both antigen-presenting cells and of B and T lymphocytes, defects in Natural Killer cell function, and broad-spectrum autoimmune disease. We will investigate the cellular and molecular basis of these phenomena. We will determine the relative contributions of Gas6 and Protein S to TAM receptor activation, and investigate the biochemical mechanisms that underlie suppression of innate immune responses by TAM signaling. We have found that a central mechanism of TAM-mediated suppression involves activation of the transcription factor STAT1 - which is also initially required to activate cytokine production. This sets up a classic negative feedback loop for the regulation of inflammation. We will also elucidate the role that TAM receptors play in triggering the phagocytosis and clearance of apoptotic cells, and dissect the extracellular and intracellular components of the pathway through which the receptors receive and transduce signals required for this process. Together, these studies will provide basic insights into a new signaling system of critical importance to the regulation of immune responses and the development of autoimmunity.

该应用程序的实验旨在阐明角色 TAM受体酪氨酸激酶-Tyro 3，Axl和Mer-在体内平衡中发挥作用对先天免疫的调节。我们发现这些受体以及它们的激动剂气体6和蛋白质S是炎症的必不可少的固有抑制剂对感染的反应。 TYRO 3，AXL和MER由巨噬细胞和树突状表达细胞（DC）。这些细胞通过产生A来应对入侵细菌和病毒促炎和炎症细胞因子的全张，虽然对病原体的失败也对正常细胞和组织有害。如果未选中先天免疫反应的终结，细胞因子（例如TNF-A）的产生导致慢性炎症性疾病和自身免疫性。提出的研究利用了一组强大的遗传试剂 - 突变小鼠缺乏每个受体和活化配体的功能。作为成年人，这些小鼠表现出毁灭性免疫缺陷，包括以严重的脾肿和淋巴结肿大，两者的全身性过度激活抗原呈递细胞以及B和T淋巴细胞的自然杀伤细胞缺陷功能和广谱自身免疫性疾病。我们将研究细胞和这些现象的分子基础。我们将确定 GAS6和蛋白质S到TAM受体激活，并研究生化通过TAM信号传导抑制先天免疫反应的机制。我们发现TAM介导的抑制的中心机制涉及转录因子STAT1的激活最初也需要激活细胞因子产生。这为调节的经典负面反馈循环设置了炎。我们还将阐明TAM受体在触发触发中的作用凋亡和凋亡细胞清除率，并剖析细胞外和受体接收的途径的细胞内成分此过程需要传递信号。这些研究将共同提供基本洞悉对免疫调节至关重要的新信号传导系统反应和自身免疫的发展。