Regulation of human IL12/IL23 responsiveness by IL12RB1

IL12RB1 对人类 IL12/IL23 反应性的调节

• 批准号: 9761425
• 负责人: Richard Robinson
• 金额: $ 37.99万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-25 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761425
• 关键词: AIDS/HIV problem; Affinity; Alternative Splicing; Antibiotic Therapy; Autoimmunity; Bacteria; Binding; Biochemical; Biological Assay; Cause of Death; Cell Differentiation process; Cell Nucleus; Cell surface; Cells; Chemosensitization; Complex; Cytokine Receptors; Data; Disease; Disulfides; Dominant-Negative Mutation; Environment; Extracellular Space; Genes; Genetic Complementation Test; Genetic Transcription; Human; IL12RB1 gene; Immune response; Immunobiology; Immunologics; Immunology; Interleukin-12; Knowledge; Link; Lung; Malignant Neoplasms; Messenger RNA; Methods; Modeling; Molecular Biology; Molecular Chaperones; Mus; Mycobacterium tuberculosis; Neutrophil Infiltration; Patients; Peripheral Blood Mononuclear Cell; Phosphorylation; Productivity; Property; Protein Isoforms; Proteins; Reagent; Receptor Signaling; Recurrence; Regulation; Reporter; Research; Research Personnel; Research Project Grants; Resistance; Signal Pathway; Signal Transduction; Site; Surface; T cell response; T-Lymphocyte; Testing; Translating; Tuberculosis; base; cytokine; extracellular; human disease; human model; in vivo; innovation; interleukin-23; macrophage; novel; pathogenic bacteria; receptor; response; transmission process; tuberculosis treatment

ABSTRACT Tuberculosis (TB) is a human disease caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb). In 2015, TB ranked above HIV/AIDs as a leading cause of death worldwide. The gene IL12RB1 regulates human resistance to TB by promoting cytokine (IL12/IL23)-dependent differentiation of naïve TH cells into TH1 and TH17 effectors. TH1 and TH17 cells limit Mtb survival by activating Mtb-infected macrophages and recruiting neutrophils to infected sites. It was established >20 years ago that IL12RB1 is transcribed and translated into IL12Rβ1, a transmembrane receptor on the TH cell surface that binds IL12/IL23, and then complexes with secondary receptors (IL12Rβ2, IL23R) to activate the intracellular signaling cascades that drive TH1/TH17 differentiation. However, we recently demonstrated that IL12RB1 is also transcribed and translated into a second isoform (Isoform 2, or Iso2) that is a secreted potentiator of IL12/IL23 activity. The mechanism whereby Iso2 potentiates IL12/IL23 activity is not known. Here, we propose a research project that will both fill important gaps in our knowledge of IL12RB1 and determine the mechanism of Iso2 potentiation. This project is significant since IL12RB1 regulates multiple immune responses including TB-resistance, and innovative since it will establish a paradigm for how natural soluble cytokine receptors potentiate cytokine activity. This project is also being pursued by an investigator with demonstrated independent expertise and productivity in the field of IL12RB1-TB interactions, in an environment that is highly supportive of basic immunology research. Finally, the methods and approach we use build on our demonstrated expertise in molecular biology, immunology and the mouse TB model. There are two Specific Aims: (AIM 1) Determine the biochemical mechanism that Isoform 2 enhances IL12/IL23 signaling; (AIM 2) Determine the immunological mechanism that Isoform 2 increases TB resistance. At the end of our studies, we will have extended our basic understanding of IL12RB1 immunobiology in the context of TB, as well as generated novel proteins with potential use as an adjunct TB therapy. Since IL12RB1's influence extends beyond TB to also include autoimmunity, cancer, and atopic disease, the mechanisms we identify are relevant to these other human diseases.

摘要 结核病（TB）是由细菌病原体结核分枝杆菌（Mtb）引起的人类疾病。在 2015年，结核病超过艾滋病毒/艾滋病，成为全球主要死亡原因。IL 12 RB 1基因调控人类 - 通过促进细胞因子（IL 12/IL 23）依赖性的幼稚TH细胞分化为TH 1和 TH 17效应器。TH 1和TH 17细胞通过激活Mtb感染的巨噬细胞和募集来限制Mtb的存活 中性粒细胞感染部位。20年前就已经确定，IL 12 RB 1转录并翻译成 IL 12 R β1，TH细胞表面上的跨膜受体，其结合IL 12/IL 23，然后与 次级受体（IL 12 R β2、IL 23 R），以激活驱动TH 1/TH 17的细胞内信号级联 分化然而，我们最近证明，IL 12 RB 1也被转录和翻译成一种蛋白质。 第二同种型（同种型2，或Iso 2），其是IL 12/IL 23活性的分泌增强剂。的机理 Iso 2增强IL 12/IL 23活性尚不清楚。在这里，我们提出了一个研究项目，既将填补重要的 我们对IL 12 RB 1的认识中的空白，并确定Iso 2增强的机制。这个项目是 由于IL 12 RB 1调节包括TB抗性在内的多种免疫应答， 因为它将建立天然可溶性细胞因子受体如何增强细胞因子活性的范例。这 一名调查员也在进行该项目，该调查员在以下方面具有独立的专门知识和生产力： IL 12 RB 1-TB相互作用领域，在高度支持基础免疫学的环境中 research.最后，我们使用的方法和途径建立在我们在分子生物学领域的专业知识基础上。 生物学、免疫学和小鼠结核病模型。有两个具体目标：（目标1）确定 同种型2增强IL 12/IL 23信号传导的生化机制;（AIM 2）确定免疫学 同种型2增加TB抗性的机制。在我们的研究结束时，我们将扩大我们的基本 在结核病背景下对IL 12 RB 1免疫生物学的理解，以及产生具有 作为结核病辅助治疗的潜在用途。由于IL 12 RB 1的影响超出了结核病， 自身免疫，癌症和特应性疾病，我们确定的机制与这些其他人类疾病有关。 疾病