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: 8145234
• 负责人: Scott Alper
• 金额: $ 19.61万
• 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/8145234
• 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; Lipopolysaccharides; Lung diseases; MAP Kinase Gene; Membrane Protein Traffic; Microscopy; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Molecular; Monitor; Mus; NF-kappaB-inducing kinase; 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 diagnostics; 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)：暴露于生物毒素可诱导先天免疫反应，并与许多炎症性疾病有关，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。利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，它们控制着一种生物毒素--脂多糖(LPS)诱导的炎性细胞因子的产生。这些新基因中的几个在线虫、小鼠巨噬细胞、小鼠和人类的天然免疫调节中显示出潜在的保守功能，表明这些保守基因在免疫调节中具有潜在的重要性。然而，我们还没有开始机制研究，以确定这些基因如何发挥作用，这是建立这些基因作为新的治疗或诊断靶点的必要前奏。根据我们的初步数据和这些基因的序列，我们推测我们鉴定的新的天然免疫基因的功能要么是通过包括核因子B激活在内的天然免疫信号机制，要么是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的R21筹资机制来进行机制研究，以阐明这些新的天然免疫调节因子的功能。具体地说，我们将确定这些新基因如何调节经典的先天免疫信号通路，包括核因子？B和MAP激酶信号的激活，以及这些基因如何调节细胞因子的运输和分泌。 公共卫生相关性：许多免疫性疾病的发病率和严重程度既受环境中生物毒素的影响，也受宿主先天免疫系统遗传因素的影响。与环境因素有关的常见免疫性疾病包括哮喘、过敏、败血症和克罗恩病。这些疾病给我们的卫生保健系统造成的死亡率和财政负担的代价是惊人的，其中包括数百万工作和上学日的损失，数十万人的生命损失，以及每年数百亿美元的支出。尤其令人头疼的是，这些疾病的发病率正在迅速增长。我们建议的目标是确定我们已经确定的几个新的先天性免疫反应调节器所利用的关键机制。这种方法将为炎症性疾病的潜在预防、诊断和治疗产生一套新的目标。

项目成果

Identifying novel spatiotemporal regulators of innate immunity.

识别新型的先天免疫时空调节剂。

• DOI: 10.1007/s12026-012-8344-0
• 发表时间: 2013-03
• 期刊: Immunologic research
• 影响因子: 4.4
• 作者: Victorino F;Alper S
• 通讯作者: Alper S

Spatiotemporal inhibition of innate immunity signaling by the Tbc1d23 RAB-GAP.

• DOI: 10.4049/jimmunol.1102595
• 发表时间: 2012-03-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: De Arras L;Yang IV;Lackford B;Riches DW;Prekeris R;Freedman JH;Schwartz DA;Alper S
• 通讯作者: Alper S

Limiting of the innate immune response by SF3A-dependent control of MyD88 alternative mRNA splicing.

• DOI: 10.1371/journal.pgen.1003855
• 发表时间: 2013-10
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: De Arras L;Alper S
• 通讯作者: Alper S