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Regulation of bone loss by IL-23/IL-17A axis in inflammatory arthritis

IL-23/IL-17A 轴对炎性关节炎中骨丢失的调节

基本信息

批准号：
8448647
负责人：
Iannis Elias Adamopoulos
金额：
$ 32.92万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448647
关键词：
Actins Adult Alleles American Animals Ankylosing spondylitis Arthritis Autoimmune Diseases Autoimmune Process Binding Bone Marrow CD4 Positive T Lymphocytes Calcium Signaling Cells Clinical Computers Cytoplasmic Tail Disease Dissection F-Actin Gene Transfer Genes Helper-Inducer T-Lymphocyte Hematopoietic Histology Human ITAM ITGAM gene ITGAX gene Immune Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-17 MDL-1 receptor Measures Mediating Memory Modeling Molecular Monitor Multiple Sclerosis Mus Myelogenous Myeloid Cell Activation Myeloid Cells Osteoclasts Pathogenesis Pathway interactions Phagocytes Phosphorylation Polymerase Population Psoriatic Arthritis RNA-Directed DNA Polymerase Reaction Regulation Reporter Research Rheumatoid Arthritis Role Serum Signal Transduction Single Nucleotide Polymorphism Sorting - Cell Movement System Systemic Lupus Erythematosus T-Lymphocyte TEC Protein Tyrosine Kinase TYROBP gene Therapeutic Intervention Translating aging population autoimmune arthritis bone bone loss cytokine design economic impact genome-wide human EMS1 protein human SYK protein in vivo insight interleukin-23 kinase inhibitor novel novel therapeutics nuclear factors of activated T-cells osteoclastogenesis prevent progenitor receptor response skeletal src-Family Kinases tomography

项目摘要

DESCRIPTION (provided by applicant): About 50 million Americans (22%) suffer from some form of arthritis and estimates are that, with the aging population worldwide, 67 million adults will have arthritis by 2030 with an economic impact higher than $128 billion dollars. Although interleukin-23 (IL-23) has been implicated in the pathogenesis of arthritis, the molecular mechanisms remain unknown. Since the discovery of IL-23 regulation of pathogenic T helper cells that express interleukin-17 (Th17) the importance of direct actions of IL-23 in arthritis is overshadowed. To highlight its importance we developed gene-transfer models of IL-23 and IL-17A and using these models we established that IL-23 is a potent inducer of arthritis, independently of IL-17A. Dissection of IL-23 from the IL- 23/IL-17A axis has allowed us to uncover novel mechanisms of myeloid cell activation previously overlooked. We identified that IL-23 induces arthritis independently of Th17 cells and through activation of myeloid cells. T cells and myeloid cells share a requirement for costimulatory signals that are mediated by ITAMs. The ITAM is a conserved signaling motif contained in the cytoplasmic domain of transmembrane adaptor molecules that are associated and transmit signals from various immunoreceptors present in haematopoietic progenitors. These signals orchestrate synovial inflammation and differentiation of myeloid cells to bone resorbing cells called osteoclasts. Discovering the cellular and molecular mechanisms that dictate recruitment and activation of osteoclasts in inflammatory arthritis is central to preventing this disabling condition. Detailed understanding of these cellular and molecular interactions will yield insights into regulation of arthritis that can be exploited for therapeutic interventions.

描述（由申请人提供）：大约5000万美国人（22%）患有某种形式的关节炎，据估计，随着全球人口老龄化，到2030年，将有6700万成年人患有关节炎，经济影响将超过1280亿美元。虽然白细胞介素-23 （IL-23）与关节炎的发病机制有关，但其分子机制尚不清楚。自从发现IL-23调节表达白细胞介素-17 （interleukin-17, Th17）的致病性T辅助细胞以来，IL-23在关节炎中的直接作用的重要性被掩盖了。为了强调其重要性，我们开发了IL-23和IL-17A的基因转移模型，并利用这些模型建立了IL-23是一种有效的关节炎诱导剂，独立于IL-17A。从IL-23 /IL- 17a轴上分离IL-23使我们发现了以前被忽视的髓细胞活化的新机制。我们发现IL-23诱导关节炎独立于Th17细胞，并通过激活髓细胞。T细胞和髓细胞对itam介导的共刺激信号有共同的需求。ITAM是一个保守的信号基序，包含在跨膜接头分子的细胞质域中，该分子与造血祖细胞中存在的各种免疫受体相关并传递信号。这些信号协调滑膜炎症和髓细胞分化为骨吸收细胞，称为破骨细胞。发现炎症性关节炎中决定破骨细胞募集和激活的细胞和分子机制是预防这种致残状况的核心。对这些细胞和分子相互作用的详细了解将产生对关节炎调节的见解，可以用于治疗干预。