Mechanisms of nematode molting

项目概要和摘要 我的研究小组的长期目标是了解线虫 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性细胞外基质（ECM）如何在 在哺乳动物的皮肤发育过程中，通过ECM告知哺乳动物的皮肤生理学、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 将探讨线虫蜕皮是否是由生殖系统调节的，这是该领域一个长期存在的问题。这项工作 也将为动物如何将发育与饮食结合起来提供基本的见解。我们也有兴趣 线虫特异性生物学，因为它提供了防治寄生线虫感染的干预点。作为一个群体， 这些动物影响了全世界约15亿人，约占全球人口的85%。 被忽视的热带病它们还通过感染农作物和牲畜威胁粮食安全。我们的长期 目标是确定在分子、细胞和生物体水平上确保可靠蜕皮的机制， C.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替换，以允许进一步生长， 需要细胞内运输，细胞外基质重塑，新外骨骼的组装，以及 刻板的一系列行为来逃避旧的外骨骼。与我们深刻理解的 虽然我们已经获得了节肢动物蜕皮的机制，但我们才刚刚开始了解 调节线虫蜕皮的基因。对线虫蜕皮的研究有望揭示蜕皮基因是如何 监管网络已经发展，并提供寄生线虫的药物干预点。 梭线虫蜕皮周期是一个振荡过程，与哺乳动物的昼夜节律相似， 受哺乳动物时钟蛋白的同源物如NHR-23（哺乳动物RORa的同源物）调节。的 C.秀丽线虫蜕皮可以根据饮食输入延长或缩短，使其成为探索如何 环境和饮食可以影响发育时间。我们将使用NHR-23作为定义上游的切入点 调节信号和下游效应物的协调作用。我们假设类固醇 激素信号传导控制NHR-23以促进启动蜕皮的振荡基因表达， 协调ECM重塑。我们的目标是测试这一假设的关键方面。在目标1中，我们确定ECM如何 蜕皮期间的重塑通过蛋白酶和蛋白酶抑制剂的协同作用来协调。在目标2中， 我们将确定在蜕皮期间振荡基因表达是如何被促进的。在目标3中，我们将测试 配体驱动线虫蜕皮，这是该领域中一个难以捉摸的问题。

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.