Investigating how sequentially acting cues guide long-distance cell migration in vivo within embryos

研究顺序作用线索如何引导胚胎体内的长距离细胞迁移

基本信息

批准号：
10223395
负责人：
Angelike Stathopoulos
金额：
$ 35.08万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
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/10223395
关键词：
Anoikis Apoptosis Area Attenuated Automobile Driving Biological Assay Biological Models Candidate Disease Gene Cell Communication Cell Death Cell Proliferation Cell Survival Cells Chemotactic Factors Chemotaxis Chromosome Mapping Congenital Abnormality Cues Data Defect Development Disease Disseminated Malignant Neoplasm Distant Drosophila genus Embryo Embryonic Development Environment Equilibrium Exhibits Fibroblast Growth Factor Fibroblast Growth Factor Receptors G-Protein-Coupled Receptors Genes Genetic Genetic Screening Human Image Integral Membrane Protein Intestines Invaded Ligands Malignant Neoplasms Mediating Mesoderm Mesoderm Cell Midgut Modeling Movement Muscle Mutation Myoblasts Names Organ Organogenesis Pathologic Pathway interactions Pattern Peptide Hydrolases Population Primordium Process Regulation Research Resistance Rest Role Signal Pathway Signal Transduction Smooth Muscle Myocytes Stereotyping Structure of primordial sex cell System Techniques Testing Time Transcript Transforming Growth Factor beta Vertebrates Visceral Visceral Myopathies attenuation bone morphogenetic protein receptors cell motility cell type cohort imaging approach in vivo innovation insight migration mutant novel optogenetics prevent programs spatiotemporal therapeutic target tool tumorigenesis

Anoikis Apoptosis Area Attenuated Automobile Driving Biological Assay Biological Models Candidate Disease Gene Cell Communication Cell Death Cell Proliferation Cell Survival Cells Chemotactic Factors Chemotaxis Chromosome Mapping Congenital Abnormality Cues Data Defect Development Disease Disseminated Malignant Neoplasm Distant Drosophila genus Embryo Embryonic Development Environment Equilibrium Exhibits Fibroblast Growth Factor Fibroblast Growth Factor Receptors G-Protein-Coupled Receptors Genes Genetic Genetic Screening Human Image Integral Membrane Protein Intestines Invaded Ligands Malignant Neoplasms Mediating Mesoderm Mesoderm Cell Midgut Modeling Movement Muscle Mutation Myoblasts Names Organ Organogenesis Pathologic Pathway interactions Pattern Peptide Hydrolases Population Primordium Process Regulation Research Resistance Rest Role Signal Pathway Signal Transduction Smooth Muscle Myocytes Stereotyping Structure of primordial sex cell System Techniques Testing Time Transcript Transforming Growth Factor beta Vertebrates Visceral Visceral Myopathies attenuation bone morphogenetic protein receptors cell motility cell type cohort imaging approach in vivo innovation insight migration mutant novel optogenetics prevent programs spatiotemporal therapeutic target tool tumorigenesis

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项目摘要

SUMMARY Collective cell migration is essential to the progression of normal embryonic development and organogenesis, and is a tightly-regulated process that can involve the interplay between two or more signaling pathways to drive forward movement of cell cohorts. Additionally, patterning an organ often requires selective apoptosis and compensatory proliferation of cells. Errors in collective migration and cell death programs can have serious consequences, including complete developmental arrest, abnormal organ function, and tumorigenesis. In this proposed research plan, we will use the Drosophila embryonic caudal visceral mesoderm (CVM), a small population of muscle precursor cells that undergo highly stereotyped directional movement, as a model for collective cell migration and survival. As the longest migration of embryogenesis, CVM cells must receive input via signaling cues from other cells in order to navigate the changing environment of the developing embryo. We have previously determined an important role for FGF signaling as both chemotropic and survival cue, and that FGF receptor is specifically expressed in a subset of migratory cells. However, loss of FGF signaling does not completely ablate collective migration, suggesting the existence of additional, as-of-yet uncharacterized cues. The objective of this study is to gain a comprehensive understanding of the spatiotemporally-regulated cues that guide directional movement of the CVM, and subsequent survival or apoptosis of distinct subsets of cells. Our central hypothesis is that FGF signaling cooperates with additional signaling cues in order to drive forward movement and cell survival, and involves defining specialized subsets of cells within each CVM cohort to promote spatial organization driving forward movement. To test this hypothesis, we will pursue the following specific aims: (AIM 1) Investigate roles for spatially-localized genes within the migrating CVM collective in promoting cell migration; (AIM 2) Investigate mechanism of CVM attraction to PGCs; and (AIM 3) Investigate the relationship between BMP and FGF signaling in regulating CVM cell migration and survival. To accomplish these aims, we will employ an innovative combination of established genetics and immunostaining techniques with elegant optogenetics and in vivo live imaging approaches to manipulate and visualize migratory cells, as well as quantify spatiotemporal activation of the cell death program. We believe this study is significant because it would not only demonstrate a mechanism for signaling cross-talk in an emerging yet poorly-characterized cell migration system, but considering the large number of functions and diseases attributed to signaling pathways such as BMP and FGF, elucidating the interaction between multiple pathways in the context of the genetically-tractable and conserved Drosophila model system has the potential to identify more specific therapeutic targets. Therefore, this study will be impactful by contributing to a more comprehensive understanding of collective cell migration, the mechanisms underlying organogenesis, as well as the cell migration and survival programs implicated in normal development and cancer.

概括集体细胞迁移对于正常胚胎发育和器官发生的发展至关重要，并且是一个严格调节的过程，可以涉及两个或多个信号通路之间的相互作用推动细胞队列的前进运动。此外，构成器官通常需要选择性凋亡和细胞的补偿性增殖。集体迁移和细胞死亡计划中的错误可能会严重后果，包括完全发育停滞，异常器官功能和肿瘤发生。在这个拟议的研究计划，我们将使用果蝇胚胎尾心内胚层（CVM），这是一个小的经历高度定型定向运动的肌肉前体细胞的种群，作为模型集体细胞迁移和生存。作为胚胎发生最长的迁移，CVM细胞必须接收输入通过来自其他单元的信号提示，以导航发育中的胚胎的不断变化的环境。我们以前已经确定了FGF信号传导的重要作用，既是趋化和生存提示，又该FGF受体在迁移细胞的一部分中特别表达。但是，FGF信号的丢失确实并非完全烧毁集体迁移提示。这项研究的目的是获得对时空调节的全面理解指导CVM方向运动的提示，以及随后的生存或凋亡的不同子集的生存或凋亡细胞。我们的中心假设是FGF信号与其他信号提示合作以驱动向前运动和细胞存活，并涉及定义每个CVM队列中细胞的专门子集促进空间组织推动前进运动。为了检验这一假设，我们将追求以下具体目的：（目标1）研究迁移的CVM集体中空间定位基因的作用促进细胞迁移；（AIM 2）研究CVM吸引对PGC的机制；（目标3）调查 BMP与FGF信号传导之间的关系在调节CVM细胞迁移和存活中的关系。完成这些目标，我们将采用既定遗传学和免疫染色技术的创新组合具有优雅的光遗传学和体内实时成像方法来操纵和可视化迁移细胞，如以及量化细胞死亡程序的时空激活。我们认为这项研究很重要因为它不仅可以证明在出现的特征较差的细胞迁移系统，但考虑了大量功能和疾病归因于信号通路，例如BMP和FGF，阐明了多个途径之间的相互作用在遗传和保守的果蝇模型系统的背景下更具体的治疗靶标。因此，这项研究将对更多的贡献产生影响对集体细胞迁移的全面理解，也有机发生的机制随着细胞迁移和生存计划与正常发育和癌症有关。