Molecular mechanisms utilized by novel innate immunity regulators

描述（由申请人提供）：暴露于生物毒素诱导先天免疫反应，并与许多炎症性疾病相关，包括过敏、哮喘、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治疗和诊断选择发展的潜在新靶点。使用比较基因组学方法，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，控制由一种生物毒素，脂多糖（LPS）诱导的炎症细胞因子的产生。这些新基因中的一些在秀丽隐杆线虫、小鼠巨噬细胞、小鼠和人类的先天免疫调节中表现出潜在的保守功能，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来确定这些基因是如何起作用的，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，我们假设我们已经确定的新的先天免疫基因要么通过描述良好的先天免疫信号机制(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，以阐明这些新型先天免疫调节因子的功能。具体来说，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NF的激活。B和MAP激酶信号，以及这些基因如何调节细胞因子的运输和分泌。

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.