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.

项目摘要/摘要 表皮生长因子（EGF）家族配体通过EGFR/ErbB受体控制的信号传导 后生动物的无数发育和行为过程及其失调有助于 人类疾病，如癌症和精神分裂症。EGF信号传导机制的研究 线虫C.几十年来，它一直是一个功能的模型， 单个配体-受体对，由lin-3/EGF和let-23/EGFR编码。EGF信号的作用 in C.线虫外阴器官发生，沿着强大的分子遗传工具， 模型系统，揭示了信号转导的基本概念。近年来，随着EGFR- 由各种形式的细胞损伤触发的依赖性睡眠状态已经在C.优美的 这种压力诱导的睡眠（SIS）已经在果蝇和斑马鱼中观察到， 代表睡眠驱动的核心组成部分。与此相一致的是，EGF家族配体已经被广泛应用于 在包括哺乳动物在内的所有物种中发现了促进睡眠的活性。然而，机制 细胞损伤通过何种方式导致促睡眠神经元内的EGFR活化尚不清楚。作为 LIN-3是C. elegans，SIS中LIN-3的需求已经被 主要是假设，而不是仔细检查。此外，尝试鉴定一种蛋白酶， 来自其膜结合前蛋白响应细胞应激的可溶性EGF结构域已经被 不成功。基于大量学生收集的数据，包括来自无偏遗传学的发现， 筛选不眠突变体，我们假设C.线虫具有额外的EGFR配体 它由应激反应金属蛋白酶ADM-4处理，以触发睡眠。我们提出了一个 严格的分子遗传学研究计划，涉及学生，旨在表征这种新的EGF 家族配体及其脱落酶。这些研究有望揭开压力诱导的 睡眠，具有跨物种的潜在相关性，并建立了一个强大的压力遗传模型- 与癌症相关的EGFR反应性激活。