Mechanisms of nematode molting

线虫蜕皮机制

基本信息

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
项目类别：
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

项目摘要

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.

项目摘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使用这些信息来了解基本的构成生物学过程。我们将确定周围所有细胞周围环境的胶原外基质（ECM）如何精确重塑发育，通过ECM告知哺乳动物皮肤生理学，伤口愈合和肿瘤侵袭。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。我们将探索线虫摩擦是否是荷尔蒙调节的，这是该领域的长期问题。这项工作还将提供有关动物夫妇如何与饮食发展的基本见解。我们也对线虫特异性生物学，因为它提供了对抗寄生线虫感染的干预点。作为一个小组这些动物遭受了全球估计有15亿人口的困扰，约占全球的85％被忽视的热带疾病。他们还通过感染的农作物和牲畜威胁粮食安全。我们的长期目标是定义确保在分子，细胞和有机水平上忠实摩擦的机制秀丽隐杆线虫，然后将我们的工作扩展到寄生线虫模型中。分s涉及对动物外骨骼的协调替换，以便进一步生长和需要细胞内贩运，细胞外基质重塑，新外骨骼组装和A 定型的一系列行为，以逃脱旧的外骨骼。与我们的深刻理解相反已经获得了节肢动物摩擦的机制，我们才开始理解调节线虫摩擦的基因。在线虫摩擦上散发光有望揭示摩擦基因的方式监管网络已经发展，并在寄生线虫中提供了药物干预点。秀丽隐杆线虫蜕皮周期是一个振荡过程，与哺乳动物昼夜节律相似，并且受哺乳动物时钟蛋白的同源物（例如NHR-23（哺乳动物RORA同源物））调节。这秀丽隐杆线虫蜕皮可以根据饮食输入而延长或缩短或缩短，这使其成为探索如何如何探索如何的宝贵模型环境和饮食会影响发展时机。我们将使用NHR-23作为定义上游的切入点监管信号和下游效应的协调作用。我们的工作假设是类固醇 Horsene信号传导控制NHR-23，以促进引发摩擦和协调ECM重塑。我们的目标测试了这一假设的关键方面。在AIM 1中，我们确定ECM如何在摩擦和蛋白酶抑制剂的协同作用中，摩擦过程中的重塑是协调的。在AIM 2中，我们将确定如何在摩擦过程中促进振荡基因表达。在AIM 3中，我们将测试是否配体驱动线虫摩擦，这是该领域难以捉摸的问题。