Mechanisms of nematode molting

线虫蜕皮机制

• 批准号: 10029596
• 负责人: Jordan David Ward
• 金额: $ 31.44万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10029596
• 关键词: Address; Affect; Animals; Area; Arthropods; Bacteria; Behavior; Binding; Biochemical; Biogenesis; Biological; Biological Assay; Biological Process; Biology; Caenorhabditis elegans; Cells; Cholesterol; Circadian Rhythms; Clock protein; Collagen; Defect; Dermal; Development; Developmental Process; Diet; Ecdysone; Ensure; Environment; Extracellular Matrix; Feedback; Foundations; Future; Gene Expression; Genes; Genome; Goals; Growth; Homologous Gene; Hormonal; Hormones; Hour; Human; Human Development; Insecta; Intervention; Ligand Binding; Ligands; Light; Livestock; Mammals; Messenger RNA; MicroRNAs; Modeling; Molecular; Molting; Monitor; Mutation; Nematoda; Nematode infections; Nuclear Hormone Receptors; Organism; Orthologous Gene; Parasitic nematode; Pattern; Peptide Hydrolases; Pharmacology; Physiology; Process; Protease Inhibitor; Proteins; Public Health; Regulator Genes; Research; Series; Signal Transduction; Signaling Molecule; Skin; Sleep; Stereotyping; Steroids; Structure; Sulfate; System; Testing; Therapeutic; Time; Tumor Cell Invasion; Work; Zona Pellucida; cancer cell; combat; design; exoskeleton; experimental study; food security; gene function; genome editing; hormonal signals; hormone regulation; human disease; insight; interest; leucine-rich repeat protein; neglected tropical diseases; novel; prevent; steroid hormone; trafficking; trait; transcription factor; wound healing

Project Summary and Abstract The long-term goal of my research group is to understand the mechanisms through which nematodes molt and to use this information to understand fundamental, conserved biological processes. We will determine how the collagenous extracellular matrix (ECM) that surrounds all cells is precisely remodeled during development, informing mammalian dermal physiology, wound healing, and tumor invasion through the ECM. We will reveal how animals coordinate precise patterns of oscillatory gene expression during development. We will explore whether nematode molting is hormonally-regulated, a long-standing question in the field. This work will also provide fundamental insight into how animals couple development with diet. We are also interested in nematode-specific biology, as it offers an intervention point to combat parasitic nematode infections. As a group, these animals afflict an estimated 1.5 billion people worldwide, comprising approximately 85% of global neglected tropical diseases. They also threaten food security by infecting crops and livestock. Our long-term goal is to define the mechanisms that ensure faithful molting at the molecular, cellular, and organismal level in C. elegans and then extend our work into parasitic nematode models. Molting involves the coordinated replacement of an animal’s exoskeleton to allow further growth and requires intracellular trafficking, extracellular matrix remodeling, assembly of the new exoskeleton, and a stereotyped series of behaviors to escape the old exoskeleton. In contrast to the deep understanding that we have gained on the mechanisms of arthropod molting, we are only beginning to understand the functions of genes that regulate nematode molting. Shedding light on nematode molting promises to reveal how molting gene regulatory networks have evolved, and to provide pharmacological intervention points in parasitic nematodes. The C. elegans molt cycle is an oscillatory process with similarities to mammalian circadian rhythms, and is regulated by homologs of mammalian clock proteins, such as NHR-23 (homolog of mammalian RORa). The C. elegans molt can lengthen or shorten depending on dietary input, making it a valuable model to explore how environment and diet can impact developmental timing. We will use NHR-23 as an entry point to define upstream regulatory signals and coordinated action of downstream effectors. Our working hypothesis is that steroid hormone signaling controls NHR-23 to promote the oscillatory gene expression that initiates molting and coordinates ECM remodeling. Our aims test key aspects of this hypothesis. In Aim 1, we determine how ECM remodeling during molting is coordinated by the concerted action of proteases and protease inhibitors. In Aim 2, we will determine how oscillatory gene expression is promoted during molting. In Aim 3, we will test whether a ligand drives nematode molting, an elusive question in the field.

项目概要和摘要 我的研究小组的长期目标是了解线虫的机制 蜕皮并利用这些信息来了解基本的、保守的生物过程。我们将确定 围绕所有细胞的胶原细胞外基质 (ECM) 是如何在过程中精确重塑的 发育，通过 ECM 为哺乳动物皮肤生理学、伤口愈合和肿瘤侵袭提供信息。 我们将揭示动物在发育过程中如何协调振荡基因表达的精确模式。我们 将探讨线虫蜕皮是否受激素调节，这是该领域长期存在的问题。这部作品 还将提供有关动物如何将发育与饮食结合起来的基本见解。我们也感兴趣 线虫特异性生物学，因为它提供了对抗寄生线虫感染的干预点。作为一个团体， 这些动物困扰着全世界约 15 亿人，约占全球人口的 85% 被忽视的热带疾病。它们还通过感染农作物和牲畜来威胁粮食安全。我们的长期 目标是确定确保在分子、细胞和有机体水平上忠实蜕皮的机制。 线虫，然后将我们的工作扩展到寄生线虫模型。 蜕皮涉及动物外骨骼的协调更换，以允许进一步生长和 需要细胞内运输、细胞外基质重塑、新外骨骼的组装以及 一系列刻板的行为来逃避旧的外骨骼。与我们深刻的理解相反 虽然我们已经了解了节肢动物蜕皮的机制，但我们才刚刚开始了解其功能 调节线虫蜕皮的基因。揭示线虫蜕皮有望揭示蜕皮基因如何 调控网络已经进化，并为寄生线虫提供药理干预点。 线虫的蜕皮周期是一个振荡过程，与哺乳动物的昼夜节律相似，并且 受哺乳动物时钟蛋白的同源物调节，例如 NHR-23（哺乳动物 RORa 的同源物）。这 线虫的蜕皮可以根据饮食输入延长或缩短，这使其成为探索如何延长或缩短蜕皮的有价值的模型 环境和饮食会影响发育时间。我们将使用 NHR-23 作为定义上游的入口点 下游效应器的调节信号和协调行动。我们的工作假设是类固醇 激素信号控制 NHR-23 促进振荡基因表达，从而启动蜕皮和 协调 ECM 重塑。我们的目标是检验这一假设的关键方面。在目标 1 中，我们确定 ECM 如何 蜕皮过程中的重塑是通过蛋白酶和蛋白酶抑制剂的协同作用来协调的。在目标 2 中， 我们将确定在蜕皮过程中如何促进振荡基因表达。在目标 3 中，我们将测试是否 配体驱动线虫蜕皮，这是该领域难以捉摸的问题。