Innate Immune Response to Environmental Endotoxin

对环境内毒素的先天免疫反应

• 批准号: 7010104
• 负责人: John W Hollingsworth
• 金额: $ 12.28万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-06 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7010104
• 关键词: alveolar macrophages; bacterial toxins; bone marrow transplantation; dendritic cells; endotoxins; environmental toxicology; enzyme linked immunosorbent assay; flow cytometry; genetic polymorphism; genetically modified animals; gram negative bacteria; immune response; immunocytochemistry; inflammation; laboratory mouse; lipopolysaccharides; lung lavage; monoclonal antibody; neutrophil; phenotype; polymerase chain reaction; pulmonary respiration; receptor expression; respiratory epithelium; respiratory hypersensitivity; toll like receptor

DESCRIPTION (provided by applicant) The primary goal of this proposal is to provide support and continued mentorship, which will facilitate the candidate 's development into an independent scientific investigator. This goal will be achieved through defined coursework, intense mentored research, and at least 75% protected research time. Using this research proposal as a platform, the candidate will gain expertise in a number of fundemental scientific techniques including: murine bone marrow transplantation, development of transgenic animals, controlled exposures to an aersolized environmental toxin, and phenotyping both the physiologic and biologic response in small animals as it relates to human disease. The broad objective of this proposal is to better understand the role of TLR4 (a transmembrane receptor for LPS) in regulating the physiologic and biologic response to inhaled endotoxin (LPS). Endotoxin is important in a number of human pulmonary diseases, including organic dust induced airway disease, pneumonia, acute lung injury, and ARDS. Understanding the basic biology leading to the innate immune response to endotoxin, could have a broad impact on the management of a number of human diseases. This proposal outlines the investigation of the importance of both cell-type specific expression of TLR4 and the biological importance of naturally occuring polymorphisms of human TLR4 to irihaled endotoxin with the following specific aims. Specific Aim 1: Determine whether TLR4 expression by inflammatory cells (macrophages, dendritic, lymphocytes, and neutrophils) or structural cells (airway epithelia, endothelia, and pneumocytes) is sufficient to maintain an intact physiologic and biologic response to inhaled LPS. Specific Aim 2: Determine whether cell specific TLR4 expression by macrophages, neutrophils, or airway epithelial cells is sufficient to maintain an intact physiologic and biologic response to inhaled LPS. Specific Aim 3: Determine the physiologic and biologic importance of polymorphisms in human TLR4 in a murine model to inhaled endotoxin.

描述（由申请人提供） 该提案的主要目标是提供支持和持续指导，这将促进候选人的发展成为独立的科学研究者。 这一目标将通过定义的课程工作，强烈的指导研究以及至少有75％的保护时间来实现。 候选人将使用该研究建议作为一个平台，将获得许多基金科学技术的专业知识，包括：鼠骨髓移植，转基因动物的发展，对植酸化的环境毒素的控制暴露，以及与人类病的小动物中的生理和生物学反应表现出来。 该提案的广泛目的是更好地了解TLR4（跨膜受体的LPS）在调节对吸入内毒素（LPS）的生理和生物学反应中的作用。 内毒素在许多人类肺部疾病中很重要，包括有机粉尘诱导的气道疾病，肺炎，急性肺损伤和ARDS。 了解导致对内毒素的先天免疫反应的基本生物学可能会对许多人类疾病的管理产生广泛的影响。 该提议概述了TLR4细胞类型特异性表达的重要性以及人类TLR4对伊拉尔内毒素的自然多态性具有以下特定目的的生物学重要性的研究。 具体目的1：确定炎性细胞（巨噬细胞，树突状，淋巴细胞和中性粒细胞）的TLR4表达是否是否足以维持对Inhaled LPS的完整生理和生物学反应。 具体目标2：确定巨噬细胞，中性粒细胞或气道上皮细胞是否足以维持对吸入的LP的完整生理和生物学反应。 特定目的3：确定鼠模型中人类TLR4中多态性的生理和生物学重要性对吸入内毒素。

项目成果

Giant cell interstitial pneumonia associated with nitrofurantoin.

与呋喃妥因相关的巨细胞间质性肺炎。

• DOI: 10.1007/s00408-005-2574-z
• 发表时间: 2006
• 期刊: Lung
• 影响因子: 5
• 作者: Hargett,CharlesWilliam;Sporn,ThomasA;Roggli,VictorL;Hollingsworth,JohnW
• 通讯作者: Hollingsworth,JohnW