Molecular mechanisms utilized by novel innate immunity regulators

新型先天免疫调节剂利用的分子机制

• 批准号: 7977056
• 负责人: Scott Alper
• 金额: $ 23.78万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7977056
• 关键词: Affect; Asthma; Atherosclerosis; Biological; Biological Assay; Biological Models; Biological Response Modifiers; Caenorhabditis elegans; Candidate Disease Gene; Cell Culture Techniques; Cells; Crohn' s disease; DNA; Data; Defect; Diagnosis; Diagnostic; Disease; Disease model; Environment; Exhibits; Expenditure; Exposure to; Funding; Funding Mechanisms; Future; Genes; Genetic; Genetic Polymorphism; Goals; Healthcare Systems; Homologous Gene; Human; Hypersensitivity; Immune; Immune System Diseases; Immune response; Immune system; In Vitro; Incidence; Infection; Inflammatory; Inflammatory Response; Knock-out; Life; Lipopolysaccharides; Lung diseases; MAP Kinase Gene; Membrane Protein Traffic; Microscopy; Mitogen-Activated Protein Kinases; Molecular; Monitor; Mus; Natural Immunity; Nematoda; Pathogenesis; Pathway interactions; Patients; Physiological; Prevention; Production; Proteins; Public Health; RNA Interference; Regulation; Regulator Genes; Reporter; Research; Role; Schools; Sepsis; Sequence Homology; Severities; Signal Pathway; Signal Transduction; System; Testing; Time; Toxin; Whole Organism; Work; base; cohort; comparative genomics; complex biological systems; cost; cytokine; gene function; human disease; in vivo; macrophage; microorganism; mortality; novel; novel therapeutics; pathogen; public health relevance; response; therapeutic development; trafficking

DESCRIPTION (provided by applicant): Exposure to biological toxins induces the innate immune response, and is associated with many inflammatory diseases, ranging from allergy and asthma to sepsis, Crohn's disease, and atherosclerosis. Our long term goal is to identify genes and regulatory mechanisms that control the innate immune response and the pathogenesis of inflammatory immune diseases. These genes and pathways represent potential novel targets for the development of therapeutic and diagnostic options. Using a comparative genomics approach, we have identified several novel genes and a novel protein interaction network that control the production of inflammatory cytokines induced by one biological toxin, lipopolysaccharide (LPS). Several of these novel genes exhibit potentially conserved function in the regulation of innate immunity in C. elegans, murine macrophages, mice, and humans, indicating the potential importance of these conserved genes in immune regulation. However, we have not yet embarked on mechanistic studies to define how these genes function, which is a necessary prelude to establishing these genes as new therapeutic or diagnostic targets. Based on our preliminary data and the sequence of these genes, we hypothesize that the novel innate immunity genes that we have identified function either through well described innate immune signaling mechanisms that include NF?B activation or through the regulation of transport and secretion of cytokines. We therefore propose to use the exploratory R21 funding mechanism to perform mechanistic studies to clarify the function of these novel innate immune regulators. Specifically, we will determine how these novel genes regulate classical innate immune signaling pathways, including the activation of NF?B and MAP kinase signaling, and how these genes regulate cytokine transport and secretion. PUBLIC HEALTH RELEVANCE: The incidence and severity of many immunological diseases is affected both by exposure to biological toxins in the environment and by host genetic factors of the innate immune system. Common immunological diseases with an environmental component include asthma, allergy, sepsis, and Crohn's disease. The cost in mortality and financial burden on our health care system due to these diseases is staggering, including millions of lost work and school days, the loss of hundreds of thousands of lives, and the expenditure of tens of billions of dollars each year. Particularly troublesome is the fact that these diseases are growing rapidly in incidence. The goal of our proposal is to identify the key mechanisms utilized by several novel regulators of the innate immune response that we have identified. This approach will yield a new set of targets for potential prevention, diagnosis, and treatment of inflammatory diseases.

描述（由申请人提供）：暴露于生物毒素诱导先天性免疫应答，并与许多炎性疾病相关，从过敏和哮喘到败血症、克罗恩病和动脉粥样硬化。我们的长期目标是确定控制先天免疫反应和炎症性免疫疾病发病机制的基因和调控机制。这些基因和途径代表了开发治疗和诊断选择的潜在新靶点。使用比较基因组学的方法，我们已经确定了几个新的基因和一个新的蛋白质相互作用网络，控制一种生物毒素，脂多糖（LPS）诱导的炎症细胞因子的生产。这些新基因中有几个在C. elegans，鼠巨噬细胞，小鼠和人类，表明这些保守基因在免疫调节中的潜在重要性。然而，我们还没有开始机制研究，以确定这些基因是如何发挥作用的，这是一个必要的前奏，建立这些基因作为新的治疗或诊断目标。基于我们的初步数据和这些基因的序列，我们假设，新的先天免疫基因，我们已经确定的功能，通过良好的先天免疫信号传导机制，包括NF？B激活或通过调节细胞因子的运输和分泌。因此，我们建议使用探索性R21资助机制进行机制研究，以澄清这些新的先天免疫调节剂的功能。具体来说，我们将确定这些新的基因如何调节经典的先天免疫信号通路，包括NF？B和MAP激酶信号传导，以及这些基因如何调节细胞因子的转运和分泌。 公共卫生关系：许多免疫性疾病的发病率和严重程度受到暴露于环境中的生物毒素和先天免疫系统的宿主遗传因素的影响。具有环境成分的常见免疫性疾病包括哮喘、过敏、败血症和克罗恩病。这些疾病造成的死亡率和医疗保健系统的财政负担是惊人的，包括数百万人失去工作和上学时间，数十万人丧生，以及每年数百亿美元的支出。特别令人不安的是，这些疾病的发病率正在迅速增加。我们的建议的目标是确定我们已经确定的先天免疫反应的几种新的调节剂所利用的关键机制。这种方法将为炎症性疾病的潜在预防、诊断和治疗提供一组新的靶点。