Genetic Determinants of Innate Immunity and Host Defense

先天免疫和宿主防御的遗传决定因素

• 批准号: 7174903
• 负责人: David Schwartz
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7174903
• 关键词: Aspergillus; Caenorhabditis elegans; RNA interference; Staphylococcus aureus; bactericidal immunity; fungal genetics; gene expression; gene expression profiling; genetic polymorphism; genetic susceptibility; genotype; host organism interaction; human tissue; immune response; immunogenetics; immunoregulation; laboratory mouse; lipopolysaccharides; microarray technology; microorganism immunology; molecular cloning; mycosis; quantitative trait loci; septicemia; tissue /cell culture; toll like receptor

The goals of this project are to identify novel genes involved in innate immunity and to determine if polymorphisms in some of these genes regulate the innate immune response to lipopolysaccharide (LPS), Staphylococcus aureus, and Aspergillus fumigatus infection in humans. We have previously shown that polymorphisms in TLR4, the receptor for LPS, are associated with hyporesponsiveness to inhaled LPS in mice and humans. We have also shown that these same polymorphisms predispose humans to Gram negative sepsis and protect them from atherosclerosis. However, our previous findings also demonstrate that sequence variants of TLR4 account for only a portion of the LPS phenotype in either mice or humans and that other genes are also involved in regulating the response to LPS. The role of host susceptibility in the initiation and severity of infections caused by Gram negative and Gram positive bacteria is incompletely understood. The overall goal of our sepsis project is to further understand why some individuals develop infection, and of those with bacteremia, why only some go on to have adverse outcomes. Similarly, very little is known about the host?s innate immune response to Aspergillus fumigatus, a fungal pathogen that causes invasive pulmonary aspergillosis in immunocompromized hosts. The overall hypothesis of this research program is that polymorphisms of genes identified either by genetic or genomic techniques following a challenge with a microbial toxin or a live organism in model systems (mice, C. elegans, and cell culture) regulate the pathophysiologic response to innate immune stimuli in humans. To test this hypothesis, gene expression and positional cloning studies will be conducted in mice and their genetic relevance will be tested in humans. We will also use RNA interference (RNAi) in two model systems, mammalian tissue culture and the nematode C. elegans, to test the physiologic and biologic importance of these genes.

该项目的目标是确定参与先天免疫的新基因，并确定其中一些基因的多态性是否调节人类对脂多糖（LPS）、金黄色葡萄球菌和烟曲霉感染的先天免疫反应。 我们先前已经表明，TLR4（LPS受体）的多态性与小鼠和人类对吸入LPS的低反应性相关。我们还表明，这些相同的多态性使人类易患革兰氏阴性脓毒症，并保护他们免受动脉粥样硬化。然而，我们以前的研究结果也表明，TLR4的序列变异只占小鼠或人类LPS表型的一部分，其他基因也参与调节对LPS的反应。 宿主易感性在革兰氏阴性菌和革兰氏阳性菌引起的感染的发生和严重程度中的作用尚不完全清楚。我们脓毒症项目的总体目标是进一步了解为什么有些人会发生感染，以及那些菌血症患者，为什么只有一些人会继续产生不良后果。同样，对宿主知之甚少？的先天免疫反应，烟曲霉，真菌病原体，导致侵袭性肺曲霉病的免疫受损的主机。 该研究计划的总体假设是，在模型系统中用微生物毒素或活生物体攻击后，通过遗传或基因组技术鉴定的基因多态性（小鼠，C. elegans和细胞培养物）调节人类对先天免疫刺激的病理生理反应。为了验证这一假设，将在小鼠中进行基因表达和定位克隆研究，并在人类中测试其遗传相关性。我们还将在两个模型系统中使用RNA干扰（RNAi），哺乳动物组织培养和线虫C。elegans，以测试这些基因的生理和生物学重要性。