Novel molecular mechanisms of cell migration in C. elegans

线虫细胞迁移的新分子机制

• 批准号: RGPIN-2017-06830
• 负责人: Culotti, Joseph
• 金额: $ 1.89万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=712468
• 关键词: Novel; molecular; mechanisms; cell; migration

During animal development, many cells must migrate in specific directions to reach specific locations where they form organs and complex tissues like the nervous system. Faulty cell migrations underlie many human disorders. We want to identify and understand novel, previously unknown molecular mechanisms involved in cell migration so we can better treat or prevent such disorders. We do this by making mutations in genes that affect cell migration of a model organism (C. elegans) in which cell migrations are easily followed microscopically and using each mutation to identify the gene responsible for the defect, which we then then clone and sequence. The information gleaned from this allows us to determine the nature of the product (usually a specific protein with human homologs) encoded by the gene. Portions of many proteins share specific amino acid sequences (aka domains) that have known functions at a molecular level, so often we can tell from the presence of such domains in a protein of interest, how that protein works. We can also deduce from the kind of cell migrations defect in the mutant (e.g. the cell wanders or is misdirected and never reaches its destination, or it fails to stop migrating in the correct place, or stops before reaching it, etc.) what role that protein plays in the migration process and compare this to the effects of mutations in other migration genes. We have recently identified mutations in genes that cause wandering or misdirected migrations at a specific stage of a multi-stage migration process. The protein products of two such genes help build sugar chains on secreted proteins, so we are beginning for the first time to understand how these sugar chains on specific proteins affect cell migration. Another gene modulates a previously known key gene that functions to guide migrating cells in the developing human central nervous system, so our studies should clarify how this modulation occurs at a molecular level. This is curiosity driven research, however, we hope (as often happens) that the knowledge gleaned from this research will eventually be applicable to understanding and treating several human developmental disorders as well as the abnormal migration of cells that occurs in metastatic cancer.

在动物的发育过程中，许多细胞必须向特定的方向迁移，到达特定的位置，在那里它们形成器官和复杂的组织，如神经系统。脂肪细胞迁移是许多人类疾病的基础。我们希望识别和理解涉及细胞迁移的新的、以前未知的分子机制，以便我们能够更好地治疗或预防此类疾病。 我们通过在影响模式生物细胞迁移的基因中进行突变来做到这一点（C。elegans），其中细胞迁移很容易在显微镜下跟踪，并使用每个突变来识别导致缺陷的基因，然后我们克隆和测序。 由此收集的信息使我们能够确定由该基因编码的产物（通常是具有人类同源物的特定蛋白质）的性质。 许多蛋白质的一部分共享特定的氨基酸序列（又名结构域），这些序列在分子水平上具有已知的功能，因此我们通常可以从感兴趣的蛋白质中存在的这些结构域中分辨出该蛋白质是如何工作的。 我们还可以从突变体中细胞迁移的类型推断出缺陷（例如，细胞游荡或被误导，从未到达目的地，或者它未能在正确的地方停止迁移，或者在到达目的地之前停止迁移等）。这种蛋白质在迁移过程中起什么作用，并将其与其他迁移基因突变的影响进行比较。 我们最近发现了在多阶段迁移过程的特定阶段导致游荡或错误迁移的基因突变。 两个这样的基因的蛋白质产物有助于在分泌的蛋白质上建立糖链，因此我们第一次开始了解特定蛋白质上的这些糖链如何影响细胞迁移。 另一个基因调节一个先前已知的关键基因，该基因的功能是引导发育中的人类中枢神经系统中的迁移细胞，因此我们的研究应该澄清这种调节如何在分子水平上发生。 这是好奇心驱动的研究，然而，我们希望（正如经常发生的那样）从这项研究中收集的知识最终将适用于理解和治疗几种人类发育障碍以及转移性癌症中发生的细胞异常迁移。