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.

先天免疫系统通过特异性免疫检测病原体来源的分子来预防感染