TAM receptor tyrosine kinases in inflammatory bowel disease

TAM 受体酪氨酸激酶在炎症性肠病中的作用

基本信息

批准号：
8515920
负责人：
Carla Rothlin
金额：
$ 37.68万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2014-09-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8515920
关键词：
Abdominal Pain Ablation Address Anti-Inflammatory Agents Anti-inflammatory Antigen-Presenting Cells Area Autoimmune Diseases Biological Biological Markers Biopsy Body Weight decreased Cell Differentiation process Cell physiology Chronic Chronic Disease Clinical Crohn&apos s disease Cytokine Receptors Detection Diagnosis Diagnostic Diarrhea Disease Disease Progression Drug Design Early Diagnosis Enzymes Feedback Fistula Gastrointestinal Diseases Gastrointestinal tract structure Genetic Goals Hemorrhage Human IFNAR1 gene Immune Immune System and Related Disorders Immune response Immune system In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Injury Intestinal Perforation Intestines Knock-out Knockout Mice Knowledge Laboratories Lead Ligands Measures Mediating Medical Modeling Molecular Molecular Target Mus Pathogenesis Pathology Pathway interactions Patients Plasma Plasma Proteins Productivity Protein Tyrosine Kinase Proteins Receptor Protein-Tyrosine Kinases Regulation Relapse Research Research Proposals Role Serum Severities Signal Pathway Signal Transduction Sodium Dextran Sulfate Stimulus System T-Cell Proliferation T-Lymphocyte Testing Therapeutic Therapeutic Intervention Time Tissues Toll-like receptors Toxic Megacolon Ulcerative Colitis Up-Regulation Western World Wild Type Mouse base cytokine drug discovery economic cost human disease in vivo mortality mouse model new therapeutic target novel pre-clinical prevent prognostic protein function public health relevance receptor response type I interferon receptor young adult

项目摘要

DESCRIPTION (provided by applicant): IBD is a group of chronic, relapsing inflammatory disorders of the gastrointestinal tract characterized by diarrhea, bleeding, abdominal pain, and weight loss. It can progress to serious complications due to severe inflammation, like intestinal perforation, fistula formation and/or toxic megacolon. The two main subtypes of IBD, Crohn's Disease and Ulcerative Colitis, afflict an estimated 1.1 million people in the US and represent two of the major gastrointestinal diseases of the Western world. Significantly, it is a disease that is primarily diagnosed in young adults, not only exacting an incalculable personal toll and annual economic cost in medical expenses, but also a considerable amount in lost productivity. There is an imperative need for identifying molecular targets relevant to the disease for better therapeutic approaches against IBD. Additionally, non-invasive diagnostic approaches need to be developed to facilitate the early diagnosis and therapeutic management of this chronic disease. Our studies focus on a novel, yet fundamental anti-inflammatory signaling pathway - TAM pathway - in antigen presenting cells (APCs) of the immune system and our objective is to better understand the function of this pathway in the context of this chronic, debilitating illness. Our goal is (i) to demonstrate an association between loss of TAM proteins and manifestation of severe disease employing established mouse models of this human disease, (ii) to understand the immunological dysfunction correlating with loss of these proteins functions and (iii) to subsequently extend these analyses beyond the pre-clinical mouse models to human patients and validate if TAM proteins can function as translational biomarkers for IBD. This project has the long-term potential to elucidate important molecular mechanisms underlying the clinical course of IBD, and to address important therapeutic and diagnostic/prognostic areas of need. PUBLIC HEALTH RELEVANCE: The TAM proteins represent an entirely novel area of research in IBD, yet they belong to the class of enzymes that are well established as tractable pharmacological targets and are attractive for rational drug design and discovery. The ligands for the TAM receptors are plasma proteins affording easy detection as potential serum biomarkers of disease state/severity. Therefore, the proposed project has considerable potential to not only elucidate the molecular mechanisms underlying the clinical course of IBD and to uncover novel therapeutic targets, but also to address important diagnostic/prognostic area of need.

描述（由申请人提供）：IBD是一组慢性，复发性的胃肠道炎性疾病，其特征是腹泻，出血，腹痛和体重减轻。由于严重的炎症，例如肠穿孔，瘘管形成和/或有毒的巨型巨型巨龙，它可能会发展为严重的并发症。 IBD的两个主要亚型，克罗恩病和溃疡性结肠炎，估计在美国有110万人，代表了西方世界的两种主要胃肠道疾病。值得注意的是，这种疾病主要是在年轻人中被诊断出来的，不仅要严格无法估量的个人通行费和医疗费用年度经济成本，而且生产率损失的数量也相当大。必须确定与疾病相关的分子靶标，以实现针对IBD的更好的治疗方法。此外，需要开发出非侵入性诊断方法，以促进这种慢性疾病的早期诊断和治疗管理。我们的研究集中于一种新颖但基本的抗炎信号通路-TAM途径 - 免疫系统的抗原呈递细胞（APC），我们的目标是在这种慢性衰弱的疾病的背景下更好地了解该途径的功能。我们的目标是（i）证明使用该人类疾病的既定小鼠模型的丧失TAM蛋白与严重疾病的表现之间的关联，（ii）了解与这些蛋白质功能丧失的免疫功能障碍与这些蛋白质功能的损失相关，而（iii）随后将这些分析扩展到临床上的小鼠模型对人类和验证者的范围内，则可以将这些分析扩展到TAM蛋白质的范围之外。该项目具有长期的潜力，可以阐明IBD临床过程的重要分子机制，并解决重要的治疗和诊断/预后需要。公共卫生相关性：TAM蛋白是IBD研究的一个完全新颖的研究领域，但它们属于酶类，这些酶被很好地确定为可拖动的药理学靶标，并且对合理的药物设计和发现具有吸引力。 TAM受体的配体是血浆蛋白，可轻松检测为疾病状态/严重程度的潜在血清生物标志物。因此，拟议的项目具有巨大的潜力，不仅可以阐明IBD临床过程和发现新颖的治疗靶标的分子机制，而且还解决了重要的诊断/预后需求领域。