TNF and Granuloma Formation in Tuberculosis

结核病中的 TNF 和肉芽肿形成

基本信息

批准号：
6859822
负责人：
Philana Ling Lin
金额：
$ 11.17万
依托单位：
CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-15 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6859822
关键词：
Mycobacterium tuberculosis cell migration chemokine chemokine receptor enzyme linked immunosorbent assay flow cytometry gene expression genetically modified animals granuloma histology immune response immunocytochemistry laboratory mouse latent bacterial disease lung neutralizing antibody polymerase chain reaction tumor necrosis factor alpha

项目摘要

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program designed to provide the education and laboratory experience required for a successful academic career in basic science research in infectious diseases. This multidisciplinary program will include formal coursework in immunology and basic science fundamentals as well as an extensive lab experience encompassing cellular, molecular and immunologic techniques. Dr. JoAnne Flynn, an internationally recognized expert in host defenses in Mycobacterium tuberculosis (Mtb) infection, will mentor the principal investigator. Research progress and career development will be reviewed quarterly by an advisory committee. Tumor necrosis factor-alpha(TNF) neutralization in acute and chronic Mtb-infected mice results in poor granuloma structure, disseminated disease and poor survival. Similar results have been observed in patients treated with anti-TNF antibody. We hypothesize that TNF neutralization dysregulates cell migration factors critical to granuloma formation and maintenance. This proposal seeks to determine the role of TNF and its influence on chemokines, chemokine receptors and adhesion molecules in the context of granuloma structure in the lungs during primary and latent Mtb infection. We will focus on chemokines, chemokine receptors and adhesion molecules induced in TH1 immune responses in the lung. We will determine how Mtb-induced production of TNF alters expression of chemokines, chemokine receptors and adhesion molecules using both in vitro and in vivo models; in this latter part we will examine changes in granuloma histology, immune phenotype and function in animal models of primary and latent Mtb infection treated with TNF neutralizing antibody. These changes will be analyzed the context of granuloma structure and host response to infection. The University of Pittsburgh provides an ideal research environment to support this training program.

描述（由申请人提供）：该提案描述了一项为期5年的培训计划，旨在提供成功的教育和实验室经验，以成功地从事传染病基础科学研究所需的学术职业。该多学科计划将包括免疫学和基础科学基础知识的正式课程以及包括细胞，分子和免疫学技术的广泛实验室经验。乔安妮·弗林（Joanne Flynn）博士是结核分枝杆菌（MTB）感染中宿主防御的国际认可专家，将指导首席研究员。研究进度和职业发展将由咨询委员会季刊。急性和慢性MTB感染的小鼠中和肿瘤坏死因子-Alpha（TNF）中和导致肉芽瘤结构不良，传播疾病和存活不良。用抗TNF抗体治疗的患者观察到了类似的结果。我们假设TNF中和失调的细胞迁移因子对肉芽瘤形成和维持至关重要。该提案旨在确定TNF及其对趋化因子，趋化因子受体和粘附分子的影响在原发性和潜在MTB感染期间肺部肉芽肿结构中的作用。我们将重点关注肺中Th1免疫反应中诱导的趋化因子，趋化因子受体和粘附分子。我们将使用体外和体内模型来确定MTB诱导的TNF产生如何改变趋化因子，趋化因子受体和粘附分子的表达；在后一部分中，我们将研究用TNF中和抗体治疗的原发和潜在MTB感染动物模型中的肉芽肿组织学，免疫表型和功能的变化。这些变化将分析肉芽肿结构的背景和宿主对感染的反应。匹兹堡大学提供了一个理想的研究环境来支持该培训计划。