TAM Receptor Regulation of Innate Immunity

TAM 受体对先天免疫的调节

• 批准号: 7534054
• 负责人: Greg E Lemke
• 金额: $ 47.88万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 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/7534054
• 关键词: Actins; Address; Adult; Agonist; Alleles; Antigen-Presenting Cells; Apoptotic; Autoimmune Diseases; Autoimmunity; 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; Human; Immune; Immune response; Immune system; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Intervention; Invaded; Knock-out; Ligands; Lupus; Lymphatic Diseases; Mediating; Methods; Molecular; Mouse Protein; Mus; Mutant Strains Mice; Natural Immunity; Natural Killer Cells; Normal Cell; Pathway interactions; Phagocytosis; Phenotype; Play; Process; Production; 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; Structure; Structure of retinal pigment epithelium; Syndrome; System; Systemic Lupus Erythematosus; T-Lymphocyte; Tissues; 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; protein function; receptor; recombinase; research study; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): 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 panoply 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-1 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. Relevance: Autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis exact a major toll on human health. Our studies have revealed that the TAM signaling system is a key regulator of the physiology of the cells that become chronically activated in these diseases, that deficient TAM signaling contributes to the development of autoimmunity, and that hyper-activation of TAM signaling may play a role in sepsis. This receptor system is therefore a novel and attractive target for therapeutic modulation and intervention in disease treatment.

描述（由申请人提供）：本申请的实验旨在阐明TAM受体酪氨酸激酶-TYRO 3，AXL和MER在先天免疫的体内稳态调节中发挥作用。我们已经发现，这些受体以及它们的激动剂气体6和蛋白质S是炎症反应对感染的必不可少的固有抑制剂。 TYRO 3，AXL和MER由巨噬细胞和树突状细胞（DCS）表达。这些细胞通过产生众多的促炎和炎症细胞因子来应对入侵细菌和病毒，虽然对病原体的失败至关重要，但对正常细胞和组织也有害。如果在先天免疫反应结束时不受检查，则产生诸如TNF-1之类的细胞因子会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 - 缺乏每个受体和活化配体功能的突变小鼠。作为成年人，这些小鼠表现出毁灭性的免疫缺陷，包括以严重的脾肿性和淋巴结病为特征的淋巴结增殖，抗原呈递细胞的全身性过度激活以及B和T淋巴细胞的全身性过度激活，自然杀伤细胞功能以及宽谱性自动疾病的自然杀伤细胞功能。我们将研究这些现象的细胞和分子基础。我们将确定GAS6和蛋白S对TAM受体激活的相对贡献，并研究通过TAM信号传导抑制先天免疫反应的生化机制。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的产生。这为调节炎症设置了经典的负反馈回路。我们还将阐明TAM受体在触发凋亡细胞的吞噬作用和清除率中所起的作用，并剖析受体接收并传播此过程所需的途径的细胞外和细胞内成分。总之，这些研究将提供基本的见解，以了解一种对免疫反应调节和自身免疫发展至关重要的新信号传导系统。 相关性：自身免疫性疾病，例如全身性红斑狼疮和类风湿关节炎，这是对人类健康的重大损失。我们的研究表明，TAM信号系统是在这些疾病中长期激活细胞生理学的关键调节剂，缺乏TAM信号传导有助于自身免疫性的发展，并且TAM信号的过度激活可能在败血症中起作用。因此，该受体系统是治疗调节和疾病治疗干预的新型且有吸引力的靶标。