Role of Tim Family Genes in Asthma and Allergic Diseases

描述(由申请人提供)：该项目的总体目标是阐明我们最近发现的称为TIMS的一个新的基因家族在哮喘发病机制中的作用。TIM基因似乎在调节CD4T细胞分化和过敏原诱导的呼吸道高反应性的发展中起着关键作用。此外，我们假设TIM基因的人类同源基因是哮喘易感基因，因为它们位于染色体5q33.2上，该区域重复与哮喘相关，并显示出显著的序列多态。此外，人类TIM1编码甲型肝炎病毒(HAV)的受体，表明CD4T细胞和TIM-1介导了先前感染HAV对特应性反应的已知保护作用。由于工业化国家甲型肝炎病毒感染的患病率大大降低，我们的发现可能解释了过去几十年哮喘患病率的上升，并强烈表明TIM1在直接调节人类哮喘和过敏的发展中发挥着重要作用。 这项拟议的研究将研究人类和小鼠系统中TIM基因家族的几个成员。在由Dale T.Umetsu领导的项目1中，我们将进行关联分析，以确定TIM1和TIM3基因多态是否与哮喘、过敏、特异性IgE或总IgE升高有关。我们还将分析甲型肝炎病毒与T淋巴细胞上的TIM-1结合时发生的细胞和分子过程，并确定甲型肝炎病毒感染如何改变CD4T细胞分化并防止哮喘的发展。在由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检测人TIM-1和TIM-3的功能。此外，我们还将表征TIM-3和TIM-1的配体。在Rosemarie H.DeKruyff领导的项目3中，我们将利用TIM1基因敲除小鼠和TIM阻断试剂的小鼠系统，直接研究TIM-1在Th2反应和过敏原诱导的呼吸道高反应性发展中的确切作用。 该计划项目汇集了一群非常强大的免疫学家，他们多年来密切合作，以及一位杰出的遗传学家和病毒学家。总而言之，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取得了非常出色的成就。这些对TIM基因的研究将表征一个非常重要的人类哮喘易感基因，并为哮喘发病机制中涉及的遗传、免疫和环境途径提供非凡的洞察力。

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.