An Immune Surveillance Network in C. elegans

项目摘要 肠上皮细胞保护宿主免受病原体的侵害，并防止过度的炎症反应 会造成附带伤害确定调节肠道炎症的细胞机制是一个 重要的第一步，以发现治疗目标，可以操纵这些生理过程， 东道主的优势。核激素受体是配体激活的转录因子， 代谢和细胞生理学的许多其他方面。然而，人们对核武器是如何使用的知之甚少。 激素受体影响肠道炎症或细菌病原体的先天识别。in C. 与其他后生动物相比， 特别是与人肠核激素受体肝细胞核同源的那些 因子4（HNF 4）。因此，这些蛋白质可能在线虫生理学中具有关键作用。在这个竞争激烈的 更新申请，我们的目标是确定核激素受体如何调节免疫激活， 病原体抗性我们将测试概念上的创新假设，核激素受体 作为病原体传感器，直接激活肠上皮细胞中的先天免疫防御。C. 秀丽线虫似乎不依赖于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 结果表明，C.至少部分原因是， 在病原体检测和免疫调节中发挥作用。 在第一个资助期内，我们发现了哺乳动物HNF4的同系物， 并激活抗病原体免疫防御。在此竞争性续约申请中，我们将测试 概念上创新的假设，即通过这种核传感病原体衍生的细菌代谢物， 激素受体是C. elegans检测其致病病原体 环境已发展到危险水平，并随时可能导致疾病（目标1）。在目标2中，我们 确定这种病原体衍生的代谢物是否是NHR-86的天然配体，其直接结合并激活 这种核激素受体，这一努力将表征第一个真正的先天免疫模式， 识别受体及其天然配体在C. elegans和de-orphan a核激素受体。最后在 目的3，我们将描述另一种HNF4同系物在先天免疫中的作用，这将为研究HNF4在先天免疫中的作用提供重要的参考。 支持这一蛋白质家族成员作为病原体传感器的创新想法， 缺乏典型的模式识别机制的有机体。 这项拟议中的研究将揭示以前未被认识的、进化上古老的 免疫激活和调节的策略，将对先天免疫的研究产生广泛的影响 在所有后生动物中。

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.