Exploring the function and shedding of a potential C. elegans Neuregulin

探索潜在的线虫神经调节蛋白的功能和脱落

• 批准号: 10629996
• 负责人: CHERYL LYNN VAN BUSKIRK
• 金额: $ 14.74万
• 依托单位: CALIFORNIA STATE UNIVERSITY NORTHRIDGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629996
• 关键词: Address; Alleles; Behavior; Behavioral; Binding; Biological Assay; Biological Models; Caenorhabditis elegans; Cells; Cellular Stress; Communities; Cysteine; Data; Defect; Dependence; Development; Disease; Drosophila genus; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Family; Genetic; Genetic Models; Genetic Research; Genetic Screening; Goals; Growth Factor Overexpression; Health; Hispanic-serving Institution; Human; Immunoglobulins; Inflammation; Integral Membrane Protein; Knock-out; Knowledge; Ligands; Lobular Neoplasia; Malignant Neoplasms; Mammals; Membrane; Metalloproteases; Modeling; Molecular; Molecular Genetics; Mutation; Nematoda; Neuregulins; Neurons; Organogenesis; Orthologous Gene; Pathway interactions; Peptide Hydrolases; Phenotype; Process; Productivity; Receptor Protein-Tyrosine Kinases; Research; Research Personnel; Role; Schizophrenia; Science; Signal Pathway; Signal Transduction; Sleep; Sleeplessness; Source; Stress; Students; Tissues; Training; Underrepresented Minority; Veins; Vulva; Zebrafish; career; cell injury; experience; extracellular; genetic analysis; human disease; innovation; insight; interest; mutant; overexpression; pressure; programs; promoter; receptor; repaired; response; tool; undergraduate research; undergraduate student; underrepresented minority student

PROJECT SUMMARY/ABSTRACT Signaling by Epidermal Growth Factor (EGF) family ligands through EGFR/ErbB receptors controls myriad developmental and behavioral processes across metazoa and its dysregulation contributes to human diseases such as cancer and schizophrenia. Our understanding of EGF signaling is founded in studies of the nematode C. elegans, which for decades has served as a model for the function of a single ligand–receptor pair, encoded by lin-3/EGF and let-23/EGFR. The central role for EGF signaling in C. elegans vulval organogenesis, along with the powerful molecular-genetic tools available in this model system, has revealed foundational concepts in signal transduction. In recent years an EGFR- dependent sleep state triggered by various forms of cellular damage has been identified in C. elegans. This stress-induced sleep (SIS) has since been observed in Drosophila and zebrafish, and may represent a core constituent of sleep drive. Consistent with this notion, EGF family ligands have been found to have sleep-promoting activity across species including mammals. However, the mechanism by which cellular damage leads to EGFR activation within sleep-promoting neurons is not known. As LIN-3 is the only recognized EGFR ligand in C. elegans, the requirement for LIN-3 in SIS has been largely assumed rather than carefully examined. Further, attempts to identify a protease that releases the soluble EGF domain from its membrane-bound proprotein in response to cellular stress have been unsuccessful. Based on considerable student-gathered data, including findings from unbiased genetic screens for sleepless mutants, we hypothesize that C. elegans possesses an additional EGFR ligand that is processed by a stress-responsive metalloprotease, ADM-4, to trigger sleep. We present a rigorous molecular-genetic research plan involving students that aims to characterize this new EGF family ligand and its sheddase. These studies are expected to demystify the initiation of stress-induced sleep, with potential relevance across species, and establish a powerful genetic model for stress- responsive EGFR activation with relevance to cancer.

项目概要/摘要 表皮生长因子 (EGF) 家族配体通过 EGFR/ErbB 受体控制发出信号 后生动物的无数发育和行为过程及其失调导致 我们对 EGF 信号传导的理解建立在癌症和精神分裂症等人类疾病的基础上。 对线虫秀丽隐杆线虫的研究，几十年来它一直作为线虫功能的模型 单一配体-受体对，由 lin-3/EGF 和 let-23/EGFR 编码 EGF 信号传导的核心作用。 线虫外阴器官发生，以及该领域可用的强大分子遗传学工具 近年来，EGFR-模型系统揭示了信号转导的基本概念。 已在秀丽隐杆线虫中发现了由各种形式的细胞损伤引发的依赖性睡眠状态。 此后在果蝇和斑马鱼中观察到了这种压力诱发的睡眠（SIS），并且可能 与这一概念一致的是，EGF 家族配体代表了睡眠驱动力的核心成分。 发现在包括哺乳动物在内的物种中具有促进睡眠的活性，但其机制尚不清楚。 细胞损伤如何导致促进睡眠的神经元内 EGFR 激活尚不清楚。 LIN-3是线虫中唯一公认的EGFR配体，SIS中对LIN-3的要求已 此外，主要是假设而不是仔细检查。 其膜结合蛋白前体响应细胞应激的可溶性 EGF 结构域已被 基于大量学生收集的数据，包括公正的遗传研究结果。 筛选不眠突变体，我们发现秀丽隐杆线虫拥有额外的 EGFR 配体 我们提出了一种由压力响应性金属蛋白酶 ADM-4 处理来触发睡眠的方法。 涉及学生的严格分子遗传学研究计划，旨在表征这种新的 EGF 家族配体及其脱落酶有望揭开应激诱导启动的神秘面纱。 睡眠，具有跨物种的潜在相关性，并建立一个强大的压力遗传模型 EGFR 激活与癌症相关。