Signaling activation and constraints in maintaining immune homeostasis

维持免疫稳态的信号激活和限制

• 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
• 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

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.

先天性免疫系统检测病原体衍生的分子，以通过专门的免疫系统预防感染。 受体。免疫受体包括细胞表面驻留的模式识别受体（PRR），如 哺乳动物中的Toll样受体（TLR）和植物中的受体激酶（RKs），以及细胞内的NOD样 受体（NLR）在植物和哺乳动物。植物PRRs检测保守的病原相关分子 模式（PAMP），而NLR识别病原体特异性效应子，最终形成统一的免疫模式。 系统PRR和NLR介导免疫的信号网络如何相互联系仍然存在 大部分未知。此外，免疫受体的缺陷或过度激活可能导致细胞死亡或 自身免疫因此，了解能够或限制PRR和NLR激活的机制， 维持免疫内稳态是特别重要的。PI的实验室开发了一系列 敏感和高通量的遗传筛选，以剖析复杂的激活和信号机制， 植物免疫，并揭示了malectin-like RKs（MLR）作为血浆中分子模块的重要性 连接PRR和NLR免疫受体的膜。PI的长期目标是阐明信号网络 利用拟南芥作为模型系统调节先天免疫反应，并扩展了如何 宿主抵御感染而不引起自身免疫性疾病。拟议的研究植根于PI以前的 这些发现和初步研究将支持一系列项目，解决几个关键知识 两个相互关联的研究领域的差距。首先，本研究将阐明PRR和NLR介导的 信号通路汇聚成相互关联和平衡的免疫反应。具体而言，项目 将从机制上解决PRR激活的MAP激酶级联如何调节NLR介导的免疫反应， 通过MLR感知不同的肽配体的稳态。第二，研究将破译 免疫基因编排通过分层的转录，转录后， 和单细胞水平的翻译后调节。这些项目将集中在如何交织在一起 翻译后修饰，包括ADP-核糖基化，泛素化和磷酸化， 免疫特异性基因转录、稳定性和翻译。跨学科研究将 为不同的本科生、研究生和博士后提供充足的培训机会。