An Immune Surveillance Network in C. elegans

线虫的免疫监视网络

基本信息

批准号：
10636871
负责人：
Read Pukkila-Worley
金额：
$ 50.25万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-22 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10636871
关键词：
Amino Acids Bacteria Binding Biological Response Modifiers Caenorhabditis elegans Cell Line Cell physiology Chemicals Cytoprotection Dangerousness Data Disease Environment Epithelial Cells Family Funding Genes Genetic Genetic Transcription Goals HNF4A gene Habitats Health Homologous Gene Human Immune Immune signaling Immunity Immunologic Surveillance Infection Inflammatory Response Injury Intestines Ligand Binding Ligand Binding Domain Ligands Metabolism Microbial Biofilms Molecular Structure Natural Immunity Nematoda Nuclear Family Nuclear Hormone Receptors Nuclear Receptors Organism Orphan Pathogen detection Pattern Recognition Pattern recognition receptor Phenazines Physiological Processes Physiology Protein Family Proteins Pseudomonas aeruginosa Resistance Role Signal Pathway Surveys Testing Tissues Toll-like receptors Work X-Ray Crystallography bacterial metabolism density gut inflammation immune activation immunoregulation innovation insight intestinal epithelium member pathogen pathogenic bacteria prevent promoter receptor function sensor surveillance network therapeutic target transcription factor treatment response

项目摘要

PROJECT SUMMARY Intestinal epithelial cells protect the host from pathogens and prevent exaggerated inflammatory responses that cause collateral injury. Defining the cellular mechanisms that regulate intestinal inflammation is an essential first step to uncover therapeutic targets that can manipulate these physiological processes to the host's advantage. Nuclear hormone receptors are ligand-activated transcription factors that regulate metabolism and many other aspects of cellular physiology. However, little is known about how nuclear hormone receptors influence intestinal inflammation or the innate recognition of bacterial pathogens. In C. elegans, the family of nuclear hormone receptors has dramatically expanded compared to other metazoans, particularly those that are homologous to the human intestinal nuclear hormone receptor hepatocyte nuclear factor 4 (HNF4). These proteins may, therefore, have critical roles in nematode physiology. In this competitive renewal application, we aim to determine how nuclear hormone receptors regulate immune activation and pathogen resistance. We will test the conceptually innovative hypothesis that nuclear hormone receptors function as pathogen sensors that directly activate innate immune defenses in intestinal epithelial cells. C. elegans does not seem to rely on canonical pattern recognition receptors (e.g., Toll-like receptors) to sense pathogen infection and activate immune defense in intestinal epithelial cells. Thus, the key implication of our findings is that the nuclear hormone receptor family in C. elegans expanded, at least in part, because of their function in pathogen detection and immune regulation. In the first funding period, we identified a homolog of mammalian HNF4 that surveys the chemical environment and activates anti-pathogen immune defenses. In this competitive renewal application, we will test the conceptually innovative hypothesis that sensing of a pathogen-derived bacterial metabolite by this nuclear hormone receptor is an ancient mechanism utilized by C. elegans to detect toxigenic pathogens in its environment that have grown to dangerous levels and are poised to cause disease (Aim 1). In Aim 2, we will determine if this pathogen-derived metabolite is a natural ligand for NHR-86 that directly binds to and activates this nuclear hormone receptor, an effort that will characterize the first bona fide innate immune pattern recognition receptor and its natural ligand in C. elegans and de-orphan a nuclear hormone receptor. Finally, in Aim 3, we will characterize the role of another HNF4 homolog in innate immunity, which will provide important support for the innovative idea that members of this protein family function as pathogen sensors in an organism that lacks canonical mechanisms of pattern recognition. The proposed study will reveal fundamental insights into previously unrecognized, evolutionary ancient strategies of immune activation and regulation that will have broad implications for the study of innate immunity in all metazoans.

项目概要肠上皮细胞保护宿主免受病原体侵害并防止过度的炎症反应造成附带伤害。定义调节肠道炎症的细胞机制是一个发现可以操纵这些生理过程的治疗靶点至关重要的第一步主办方的优势。核激素受体是配体激活的转录因子，调节新陈代谢和细胞生理学的许多其他方面。然而，人们对核能如何发挥作用却知之甚少。激素受体影响肠道炎症或细菌病原体的先天识别。在C. 与其他后生动物相比，线虫的核激素受体家族已显着扩大，特别是那些与人肠核激素受体肝细胞核同源的因子 4 (HNF4)。因此，这些蛋白质可能在线虫生理学中具有关键作用。在这场竞争激烈的更新应用程序，我们的目标是确定核激素受体如何调节免疫激活和病原体抵抗力。我们将测试概念上的创新假设，即核激素受体作为病原体传感器，直接激活肠上皮细胞的先天免疫防御。 C. 线虫似乎并不依赖典型的模式识别受体（例如 Toll 样受体）来感知病原体感染并激活肠上皮细胞的免疫防御。因此，我们的关键含义是研究结果表明，秀丽隐杆线虫的核激素受体家族扩大了，至少部分是因为它们具有病原体检测和免疫调节等功能。在第一个资助期间，我们鉴定了哺乳动物 HNF4 的同源物，可以调查化学环境并激活抗病原体免疫防御。在这个竞争性续订应用程序中，我们将测试概念上创新的假设是通过这种核来感知病原体衍生的细菌代谢物激素受体是秀丽隐杆线虫用来检测其体内产毒病原体的一种古老机制。环境已发展到危险水平并可能引发疾病（目标 1）。在目标 2 中，我们将确定这种病原体衍生的代谢物是否是 NHR-86 的天然配体，可直接结合并激活这种核激素受体，将成为第一个真正的先天免疫模式的特征识别受体及其天然配体。秀丽隐杆线虫和去孤儿核激素受体。最后，在目标 3，我们将表征另一种 HNF4 同源物在先天免疫中的作用，这将提供重要的信息支持这一创新想法，即该蛋白质家族的成员在细菌中充当病原体传感器缺乏模式识别规范机制的生物体。拟议的研究将揭示对以前未被认识的古代进化论的基本见解免疫激活和调节策略将对先天免疫的研究产生广泛的影响在所有后生动物中。