Signaling activation and constraints in maintaining immune homeostasis

维持免疫稳态的信号激活和限制

基本信息

批准号：
10619849
负责人：
Ping He
金额：
$ 39万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10619849
关键词：
ADP ribosylation Address Animals Arabidopsis Architecture Area Autoimmune Diseases Autoimmunity Biochemical Biological Models Cell Death Cell membrane Cell surface Cells Complex Defect Genes Genetic Genetic Screening Genetic Transcription Goals Homeostasis Immune Immune response Immune signaling Immune system Immunity Immunologic Receptors Infection Infection prevention Innate Immune Response Innate Immune System Insecta Interdisciplinary Study Knowledge Laboratories Ligands Link MAP Kinase Modules Mammals Mediating Medical Research Mission Molecular Natural Immunity Pathogen detection Pattern Pattern recognition receptor Peptides Perception Phosphorylation Phosphotransferases Plants Post-Translational Protein Processing Post-Translational Regulation Postdoctoral Fellow Receptor Activation Research Series Signal Pathway Signal Transduction Toll-like receptors Translations Ubiquitination United States National Institutes of Health combinatorial graduate student immune activation microbial pathogen posttranscriptional receptor receptor-mediated signaling training opportunity undergraduate student

项目摘要

The innate immune system detects pathogen-derived molecules to prevent infections via specialized immune receptors. The immune receptors include cell surface-resident pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) in mammals and receptor kinases (RKs) in plants, and intracellular NOD-like receptors (NLRs) in plants and mammals. Plant PRRs detect conserved pathogen-associated molecular patterns (PAMPs), whereas NLRs recognize pathogen-specific effectors, culminating in a unified immune system. How the signaling networks underlying PRR- and NLR-mediated immunity are interconnected remains largely unknown. In addition, defects or over-activation of immune receptors could lead to cell death or autoimmunity. Thus, understanding the mechanisms that enable or constrain PRR and NLR activation for maintaining immune homeostasis is particularly important. The PI’s laboratory has developed a series of sensitive and high-throughput genetic screens to dissect the complex activation and signaling mechanisms in plant immunity, and revealed the importance of malectin-like RKs (MLRs) as a molecular module at the plasma membrane linking PRR and NLR immune receptors. PI’s long-term goal is to elucidate the signaling networks regulating innate immune responses using Arabidopsis as a model system and expand the knowledge of how hosts fend off infections without causing autoimmune disorders. The proposed research rooted in PI’s previous discoveries and preliminary studies will support a series of projects that address several critical knowledge gaps in two interrelated research areas. First, the research will elucidate how the PRR- and NLR-mediated signaling pathways converge into an interconnected and balanced immune response. Specifically, the projects will mechanistically address how a PRR-activated MAP kinase cascade regulates NLR-mediated immune homeostasis through MLRs perceiving different peptide ligands. Second, the research will decipher the immune gene orchestration through the combinatorial action of the layered transcriptional, posttranscriptional, and posttranslational regulations at the single-cell level. The projects will focus on how intertwined posttranslational modifications, including ADP-ribosylation, ubiquitination, and phosphorylation, regulate immune-specific gene transcription, stability, and translation. The proposed interdisciplinary research will provide ample training opportunities for diverse undergraduate and graduate students and postdoctoral fellows.

先天免疫系统检测病原体衍生分子，通过专门的免疫来预防感染免疫受体包括细胞表面驻留的模式识别受体（PRR），例如哺乳动物中的 Toll 样受体 (TLR) 和植物中的受体激酶 (RK) 以及细胞内 NOD 样受体植物和哺乳动物中的受体（NLR）检测保守的病原体相关分子。模式（PAMP），而 NLR 识别病原体特异性效应器，最终形成统一的免疫系统 PRR 和 NLR 介导免疫的信号网络如何相互关联仍然存在。此外，免疫受体的缺陷或过度激活可能导致细胞死亡或死亡。因此，了解促进或限制 PRR 和 NLR 激活的机制。维持免疫稳态尤为重要。PI的实验室开发了一系列的产品。敏感和高通量的遗传筛选，以剖析复杂的激活和信号传导机制植物免疫，并揭示了类 malectin RK（MLR）作为等离子体分子模块的重要性连接 PRR 和 NLR 免疫受体的膜 PI 的长期目标是阐明信号网络。使用拟南芥作为模型系统调节先天免疫反应，并扩展如何调节先天免疫反应的知识宿主在不引起自身免疫性疾病的情况下抵御感染。这项拟议的研究源于 PI 之前的研究。发现和初步研究将支持一系列解决几个关键知识的项目首先，该研究将阐明 PRR 和 NLR 是如何介导的。具体而言，这些项目将信号通路汇聚成相互关联且平衡的免疫反应。将机械地解决 PRR 激活的 MAP 激酶级联如何调节 NLR 介导的免疫其次，该研究将破译 MLR 感知不同肽配体的稳态。通过分层转录、转录后、这些项目将重点关注如何相互交织。翻译后修饰，包括 ADP-核糖基化、泛素化和磷酸化，调节免疫特异性基因转录、稳定性和翻译。为不同的本科生、研究生和博士后提供样本培训机会。