Connecting transcriptional control to mechanisms of morphogenesis

将转录控制与形态发生机制联系起来

基本信息

批准号：
10398905
负责人：
Porfirio Fernandez
金额：
$ 4.68万
依托单位：
NEW YORK UNIVERSITY
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：
2020-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10398905
关键词：
3-Dimensional Actins Actomyosin Address Adhesions Adolescent Adult Advisory Committees Affect Animals Anterior Area Binding Biological Biological Models Biomedical Research Caenorhabditis elegans Candidate Disease Gene Cell Nucleus Cell Polarity Cell Shape Cell fusion Cell membrane Cell physiology Cells Cellular biology ChIP-seq Communication Computer software Congenital Abnormality Cues Cytology Cytoskeleton Data Development Developmental Biology Disease Educational Curriculum Educational process of instructing Epithelial Equipment Ethics Experimental Designs Extracellular Matrix Future Gene Expression Genes Genetic Genetic Transcription Genomics Goals Growth and Development function Hermaphroditism Image Analysis Individual Intervention Investigation Journals Knowledge Lasers Leadership Malignant Neoplasms Medicine Mentors Modeling Molecular Molecular Biology Morphogenesis Myosin ATPase Natural regeneration Oral Outcome Pharmacologic Substance Positioning Attribute Process Reporter Research Research Personnel Resources Role Scientist Shapes Specificity Structure Students System Systems Biology Tail Technology Testing Time Tissues Training Transcriptional Regulation Underrepresented Minority United States National Institutes of Health Validation Work career collaborative environment differential expression doctoral student experience gene regulatory network genetic manipulation in vivo insight knock-down male migration network architecture network models new therapeutic target notch protein pre-doctoral protein biomarkers sex skills symposium tool trafficking transcription factor transcription regulatory network transcriptome sequencing wound healing

项目摘要

PROJECT SUMMARY / ABSTRACT Cellular morphogenesis is essential to animal development and growth as well as wound healing and cancer. During this process, cells coordinately change shape, migrate, and may fuse. Cellular morphogenesis is executed by molecules called "effectors" involved in junctions, cytoskeleton, cell polarity, vesicular trafficking, and other modules/processes of the cytological machinery. The sex-, tissue-, position-, and time- specificity of morphogenesis is determined by "regulators", such as transcription factors. How transcription factors connect to and coordinate the cellular effectors to control morphogenesis is a major knowledge gap in the field. Here, the overall objective is to elucidate this connection for an experimentally accessible model structure, the tail tip of C. elegans. The tail tip is made of 4 cells which, in males only, radically alter their shape and position at the juvenile-to-adult transition, a process called Tail Tip Morphogenesis (TTM). Prior studies showed that the transcription factor DMD-3 is a master regulator (required and sufficient) for TTM and is predicted to coordinate several underlying modules/ processes of the cytological machinery. The overall approach is to determine what effectors are directly transcriptionally regulated by DMD-3 and to determine their respective functional roles in TTM, i.e. which cytological modules they affect. Aim 1 is to identify the direct target genes of DMD-3 by ChIP-seq and validate at least some of them. Aim 2 is to determine what roles at least a few DMD-3-controlled genes have in TTM by genetically perturbing them and using a toolkit of cellular markers to identify what cytological processes are governed by these effectors. The expected outcome is a network system model showing how transcriptional regulation is connected to—i.e. how it coordinates—the various parts of the cell machinery underylying TTM, thus addressing the major knowledge gap noted above. These results are expected to have a positive impact on medicine, as they could identify key conserved genes that control particular aspects of morphogenesis. Such genes could provide new targets for drugs to mitigate the effects of birth defects or cancer, or to aid wound healing. For the underrepresented minority predoctoral student responsible for carrying out all the research proposed above, the goals of the integrated training plan are to (1) deepen knowledge in the fields of molecular, cell and developmental biology, (2) gain skills in ethically and scientifically rigorous experimental design and execution, (3) hone oral and written communication skills, (4) augment leadership and mentoring skills, and (5) transition toward an independent career in biomedical research. This training will be carried out using the above research as a platform for one- on-one mentoring, coursework, journal clubs, seminars, an advisory committee, teaching experience, conferences, retention mechanisms and many other resources. This training will occur in a nurturing, collaborative environment with state-of-the-art facilities and equipment, high-quality NIH-supported curricula in developmental systems biology, and a proven record of producing diverse, top-notch scientists.

项目概要/摘要细胞形态发生对于动物的发育和生长以及伤口愈合和愈合至关重要。在此过程中，细胞协调地改变形状、迁移并可能融合。由参与连接、细胞骨架、细胞极性、囊泡的“效应器”分子执行运输以及细胞学机器的其他模块/过程性别、组织、位置和时间。形态发生的特异性是由“调节因子”决定的，例如转录因子如何转录。连接并协调细胞效应器以控制形态发生的因素是主要的知识空白在这里，总体目标是阐明实验上可访问模型的这种联系。线虫的尾尖结构尾尖由 4 个细胞组成，仅在雄性中会从根本上改变其形状。以及幼年到成年过渡时的位置，这一过程称为尾尖形态发生（TTM）。表明转录因子 DMD-3 是 TTM 的主要调节因子（必需且充足），并且预计可以协调细胞学机器的几个底层模块/过程。方法是确定哪些效应子直接受 DMD-3 转录调节并确定它们在 TTM 中各自的功能作用，即它们影响哪些细胞学模块，目标 1 是确定直接作用。通过 ChIP-seq 检测 DMD-3 的靶基因并验证其中的至少一些基因目标 2 是确定其作用。通过基因扰动并使用细胞工具包，至少有一些 DMD-3 控制的基因处于 TTM 状态。标记来识别哪些细胞学过程是由这些效应器控制的。网络系统模型显示转录调控如何连接（即如何协调） TTM 背后的细胞机制的各个部分，从而解决了上述的主要知识差距。这些结果预计将对医学产生积极影响，因为它们可以识别关键的保守基因控制形态发生的特定方面的基因可以为药物提供新的靶点来缓解。出生缺陷或癌症的影响，或帮助伤口愈合。负责开展上述所有研究的学生，综合培训计划的目标是为了 (1) 加深分子、细胞和发育生物学领域的知识，(2) 获得以下方面的技能道德和科学严格的实验设计和执行，（3）磨练口头和书面能力沟通技巧，(4) 增强领导和指导技能，以及 (5) 向独立过渡该培训将利用上述研究作为一个平台进行。一对一指导、课程作业、期刊俱乐部、研讨会、咨询委员会、教学经验、会议、保留机制和许多其他资源。拥有最先进设施和设备的协作环境、NIH 支持的高质量课程发育系统生物学，以及培养多样化、顶尖科学家的良好记录。