Mechanisms of nematode molting

项目摘要和摘要 我的研究小组的长期目标是了解线虫 并利用这些信息来理解基本的、保守的生物过程。我们将决定 所有细胞周围的胶原性细胞外基质(ECM)是如何在 通过细胞外基质发育、告知哺乳动物皮肤生理学、伤口愈合和肿瘤侵袭。 我们将揭示动物如何在发育过程中协调精确的振荡基因表达模式。我们 将探索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 还将提供对动物如何将发育与饮食相结合的基本见解。我们还感兴趣的还有 线虫特有的生物学，因为它提供了一个抗击寄生线虫感染的干预点。作为一个群体， 据估计，全球有15亿人受到这些动物的困扰，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。我们的长期合作 目标是定义在分子、细胞和组织水平上确保忠实蜕皮的机制。 然后将我们的工作扩展到寄生线虫模型。 蜕皮涉及到动物外骨骼的协调更换，以允许进一步的生长和 需要细胞内运输，细胞外基质重塑，组装新的外骨骼，以及 一系列刻板印象的行为来逃避旧的外骨骼。与我们的深刻理解相反，我们 节肢动物蜕皮的机制已经有了进展，但我们才刚刚开始了解节肢动物蜕皮的功能 调节线虫蜕皮的基因。揭示线虫蜕皮有望揭示蜕皮基因 调控网络已经进化，并为寄生线虫提供了药理干预点。 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控，如NHR-23(哺乳动物RORA的同源物)。这个 线虫的蜕皮可以根据饮食的投入而延长或缩短，这使其成为一个有价值的模型来探索如何 环境和饮食会影响发育时机。我们将使用NHR-23作为入口点来定义上游 调节信号和下游效应器的协调行动。我们的假设是类固醇 激素信号控制NHR-23促进启动蜕皮和 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水解酶和蛋白水解酶抑制物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振荡基因的表达是如何被促进的。在目标3中，我们将测试一个 配体驱动线虫蜕皮，这在该领域是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.