Role of TL1A in Severity of Crohn's Disease Inflammation

TL1A 在克罗恩病炎症严重程度中的作用

• 批准号: 7760480
• 负责人: Stephan R. Targan
• 金额: $ 41.57万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-20 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760480
• 关键词: Affect; Allergic; American; Antibodies; Antibody Formation; Antigen-Antibody Complex; Antigen-Presenting Cells; Autophagocytosis; Cell Communication; Cells; Chronic; Colitis; Complex; Crohn' s disease; Data; Development; Disease; Disease susceptibility; Encephalomyelitis; Endocytosis; Environment; Ethnic group; Event; Experimental Autoimmune Encephalomyelitis; Foundations; Generations; Genes; Genetic Variation; Genotype; Grant; Haplotypes; Human; Immune system; Individual; Inflammation; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestines; Investigation; Lamina Propria; Lead; Ligands; Lung Inflammation; Mediating; Messenger RNA; Methods; Modeling; Molecular; Mononuclear; Mucosal Immune Responses; Mucositis; Mucous Membrane; Mus; Myelogenous; Myeloid Cells; Pathogenesis; Pathway interactions; Patients; Physiological Processes; Play; Population; Predisposition; Proteins; Rheumatoid Arthritis; Role; Series; Serum; Severities; Shapes; Signal Transduction; T-Cell Activation; T-Lymphocyte; Techniques; Technology; Testing; Therapeutic; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Variant; base; commensal microbes; cytokine; genetic regulatory protein; genome wide association study; in vivo; member; mouse model; pathogenic bacteria; prevent; protein expression; public health relevance; receptor; response; therapeutic target

DESCRIPTION (provided by applicant): Inflammatory bowel diseases (IBD) are the result of complex interactions between susceptibility and severity genes, the environment and the mucosal immune system. These interactions lead to an exaggerated mucosal immune response to constituents of the commensal flora. With the advent of high-throughput molecular technologies, several genome wide association studies (GWAS) have begun to define critical molecules and pathways that converge in physiologic processes that lead to mucosal inflammation. This technique can also be used to focus in vivo mouse studies for eventual development of targeted therapeutics for defined subsets of Crohn's disease (CD) patients. Tumor necrosis factor superfamily member 15 (TNFSF15) is the only one of the several recently discovered CD associated genes that is present in all ethnic groups. The product of the TNFSF15 gene, TL1A, has been defined as a master regulatory protein that plays a key role in human intestinal inflammation. Recent studies have also defined a critical role for TL1A in the pathogenesis of mouse experimental autoimmune encephalomyelitis (EAE), models of allergic lung inflammation and human rheumatoid arthritis. During the last grant cycle, we have generated a large body of data showing the importance of TL1A in human CD. We determined that TL1A is elevated in lamina propria mononuclear cells from the mucosa of patients with CD but the level varies among individual patients with similar amounts of inflammation. GWAS established that TNFSF15 is a CD susceptibility/severity gene. We demonstrated that antibodies to TL1A prevented and treated chronic colitis by decreasing Th1 and Th17 responses in two T cell mediated mouse models, confirming a role for TL1A in severity of inflammation. Finally, we found that the level TL1A protein expression varies in association with different CD genotypes, as defined by ethnic background, haplotype and serum antibody responses. Our hypothesis is that myeloid (antigen presenting cell, APC) generation of TL1A is a dominant event that determines the severity of chronic intestinal inflammation by enhancing intestinal Th1 and Th17 responses, leading to exacerbated inflammation in CD. Further elucidation of the in vivo cellular and molecular mechanisms of TL1A function in mucosal inflammation, the mechanisms of optimal bacterial induction of TL1A, and the relationship of genetic variation in the TNFSF15 gene to maximal ligand induced TL1A protein expression will help us to identify subsets of CD patients most likely to benefit from therapeutic inhibition of TL1A function. The following Specific Aims will test this hypothesis.1) Determine the in vivo role of myeloid v. T cell expression of TL1A in the development and severity of chronic colitis in the mouse. 2) Determine the roles of endocytosis and autophagy in the bacterial induction of maximal TL1A expression in human and murine (myeloid) APC. 3) Determine the relationship between variants in the CD associated TNFSF15 gene and the level of expression of TL1A mRNA and protein in human myeloid cell populations. PUBLIC HEALTH RELEVANCE: Inflammatory bowel diseases (IBD) affects more than 1,000,000 Americans. The studies of the role of Tumor necrosis factor superfamily member 15 (TNFSF15, TL1A) in severity of inflammation in Crohn's disease potentially could lead to the development of targeted therapeutics for a defined patient subpopulation.

描述（由申请人提供）：炎症性肠病（IBD）是易感性和严重性基因，环境和粘膜免疫系统之间复杂相互作用的结果。这些相互作用导致对共生菌群成分的粘膜免疫反应。随着高通量分子技术的出现，几项基因组广泛的关联研究（GWAS）已开始定义关键分子和途径，这些分子和途径在生理过程中融合，从而导致粘膜炎症。该技术还可以用于重点进行体内小鼠研究，以最终开发针对克罗恩病（CD）患者的定义亚群的靶向疗法。肿瘤坏死因子超家族成员15（TNFSF15）是所有种族中存在的几个最近发现的CD相关基因之一。 TNFSF15基因TL1A的乘积已被定义为一种主调节蛋白，在人肠炎中起关键作用。最近的研究还确定了TL1A在小鼠实验性自身免疫性脑脊髓炎（EAE），过敏性肺部炎症和人类类风湿关节炎模型中的发病机理中的关键作用。在上一个赠款周期中，我们产生了大量数据，显示了人类CD中TL1A的重要性。我们确定来自CD患者粘膜的固有层单核细胞中TL1A升高，但炎症量相似的个别患者的水平有所不同。 GWAS确定TNFSF15是CD敏感性/严重性基因。我们证明了TL1A的抗体通过在两个T细胞介导的小鼠模型中降低Th1和Th17反应来预防和治疗慢性结肠炎，从而证实了TL1A在炎症严重程度中的作用。最后，我们发现水平TL1A蛋白表达与不同的CD基因型相关，如种族背景，单倍型和血清抗体反应所定义。我们的假设是，TL1A的髓样（抗原呈递细胞，APC）是一个主要事件，它通过增强肠道TH1和Th17反应来决定慢性肠道炎症的严重性，从而导致CD中的炎症加剧。进一步阐明TL1A功能在粘膜炎症中的体内细胞和分子机制，最佳细菌诱导TL1A的机制以及TNFSF15基因在TNFSF15基因对最大配体诱导的TL1A蛋白表达的最大性TL1A蛋白表达的关系，有助于我们识别CD cd的最大症状。以下具体目的将检验这一假设。1）确定髓样案TL1A的体内作用TL1A在小鼠慢性结肠炎的发育和严重程度中。 2）确定内吞作用和自噬在人和鼠（髓样）APC中最大TL1A表达的细菌诱导中的作用。 3）确定CD相关的TNFSF15基因中的变体与人髓样细胞群体中TL1A mRNA和蛋白质的表达水平之间的关系。公共卫生相关性：炎症性肠道疾病（IBD）影响了100万美国人。肿瘤坏死因子超家族成员15（TNFSF15，TL1A）在克罗恩病严重程度上的作用可能导致定义的患者亚群的靶向疗法的发展。