Role of Tim Family Genes in Asthma and Allergic Diseases

描述（由申请人提供）：本计划项目的总体目标是阐明我们最近发现的一个新的基因家族（称为Tims）在哮喘发病机制中的作用。Tim基因似乎在调节CD 4 T细胞分化和过敏原诱导的气道高反应性的发展中起关键作用。此外，我们假设，人类同源的蒂姆基因是哮喘易感基因，因为它们位于染色体5q33.2，一个区域反复与哮喘，并显示显着的序列多态性。此外，人类TIM 1编码甲型肝炎病毒（HAV）的受体，表明CD 4 T细胞和TIM-1介导了已知的HAV感染对特应性发展的保护作用。由于HAV感染的流行率在工业化国家大大降低，我们的研究结果可以解释过去几十年来哮喘流行率的增加，并强烈表明Tim 1在直接调节人类哮喘和过敏的发展中起着重要作用。 拟议的研究将检查人类和小鼠系统中Tim基因家族的几个成员。在项目1中，由Dale T. Umetsu，我们将进行关联分析，以确定Tim 1和Tim 3基因多态性是否与哮喘，过敏，特异性IgE或总IgE升高相关。我们还将分析HAV与T淋巴细胞上的TIM-1结合时发生的细胞和分子过程，并确定HAV感染如何改变CD 4 T细胞分化并预防哮喘的发展。在Gordon J. Freeman领导的项目2中，我们将研究人TIM-1和TIM-3的表达模式，并使用TIM-1和TIM-3融合蛋白以及针对这些蛋白的抗体来研究人TIM-1和TIM-3的功能。此外，我们将表征TIM-3和TIM-1的配体。在项目3中，由Rosemarie H. DeKruyff，我们将利用Tim 1基因敲除小鼠和TIM阻断剂的小鼠系统直接研究TIM-1在Th 2应答和变应原诱导的气道高反应性发展中的确切作用。 这个计划项目汇集了一群非常强大的免疫学家，他们与一位杰出的遗传学家和病毒学家沿着密切合作多年。这些研究人员在哮喘和过敏、克隆基因及其配体以及研究复杂疾病的遗传学方面都有很好的成绩。Tim基因的这些研究将描述一个非常重要的人类哮喘易感基因，并提供非凡的洞察参与哮喘发病机制的遗传，免疫和环境途径。

DESCRIPTION (provided by applicant): The overall goal of this Program Project is to elucidate the role of a novel family of genes that we recently discovered called Tims, in the pathogenesis of asthma. The Tim genes appear to play a critical role in regulating CD4 T cell differentiation and the development of allergen-induced airway hyperreactivity. In addition, we hypothesize that the human homologues of the Tim genes are asthma susceptibility genes, since they lie on chromosome 5q33.2, a region repeatedly linked to asthma, and display significant sequence polymorphisms. Moreover, the human Tim1 encodes the receptor for the hepatitis A virus (HAV), suggesting that CD4 T cells and TIM-1 mediate the known protective effect of prior infection with HAV on the development of atopy. Since the prevalence of HAV infection is greatly reduced in industrialized countries, our findings may explain the increase in asthma prevalence occurring over the past decades, and strongly suggest that Tim1 plays a major role in directly regulating the development of human asthma and allergy. The proposed studies will examine several members of the Tim gene family in both human and murine systems. In Project 1, headed by Dale T. Umetsu, we will perform association analysis to determine if Tim1 and Tim3 gene polymorphisms are associated with asthma, allergy, specific IgE, or elevated total IgE. We will also analyze the cellular and molecular processes that occur when HAV binds to TIM-1 on T lymphocytes, and determine how HAV infection alters CD4 T cell differentiation and prevents the development of asthma. In Project 2, headed by Gordon J. Freeman, we will examine the expression pattern of human TIM-1 and TIM-3, and examine the function of human TIM-1 and TIM-3 using TIM-1 and TIM-3 fusion proteins, as well as antibody directed against these proteins. In addition, we will characterize the ligand for TIM-3 and TIM-1. In Project 3, headed by Rosemarie H. DeKruyff, we will utilize a murine system with Tim1 knockout mice and TIM blocking reagents to directly study the precise role of TIM-1 in the development of Th2 responses and allergen-induced airway hyperreactivity. This Program Project brings together a group of very strong immunologists, who have worked closely together for many years, along with an outstanding geneticist and virologist. Together, these investigators have a very strong record of accomplishment in asthma and allergy, cloning genes and their ligands, and in investigating the genetics of complex disease. These studies of Tim genes will characterize a very important human asthma susceptibility gene, and provide extraordinary insight into genetic, immunologic and environmental pathways involved in asthma pathogenesis.