Regulating cell fate and shaping the body plan during morphogenesis and their alteration during oncogenesis

在形态发生过程中调节细胞命运并塑造身体计划及其在肿瘤发生过程中的改变

• 批准号: 9071128
• 负责人: Mark A. Peifer
• 金额: $ 37.41万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9071128
• 关键词: Actins; Actomyosin; Address; Adenomatous Polyposis Coli; Animals; Architecture; Area; Biochemical; Biological Models; Biology; Buffers; Bulla; Cancer Etiology; Cell Adhesion; Cell Communication; Cell Shape; Cell-Cell Adhesion; Cells; Cessation of life; Chromosome Segregation; Colon Carcinoma; Complex; Congenital Abnormality; Cytoskeleton; Development; Drosophila genus; Endometrial Neoplasms; Ensure; Epithelial; Epithelial Cells; Event; Funding; Genes; Genetic; Genome Stability; Goals; Homeostasis; Individual; Intercellular Junctions; Knowledge; Link; Lung Neoplasms; Malignant Neoplasms; Mammalian Cell; Microcephaly; Mitotic; Modeling; Morphogenesis; Mutate; Mutation; Neoplasm Metastasis; Organ; Phosphorylation; Play; Proteins; Regulation; Research; Role; Shapes; Signal Pathway; Signal Transduction; Structure; Tissues; Tumor Suppressor Proteins; body system; cell motility; congenital heart disorder; human disease; intercellular communication; interdisciplinary approach; meetings; nerve stem cell; public health relevance; skin disorder; tool; tumorigenesis; ubiquitin-protein ligase; zygote

 DESCRIPTION (provided by applicant): For the past 23 years, our lab has focused on one of biology's central questions--how does the single cell zygote self-assemble itself into the complex body plan of an animal? Beginning with the dual functions of ß- catenin in cell adhesion and Wnt signaling, we focused our research in two different areas. In our first project, we explore how cells utilize cell-cell interactions to change shape, move, and assemble polarized tissues during morphogenesis and maintain these during tissue homeostasis, and how cells integrate different tools in the complex actin regulatory toolkit to create diverse actin structure. We explore this in Drosophila, using a highly multidisciplinary approach, and recently expanded to include parallel studies in cultured mammalian cells. Proteins on which we focus play key roles in mammalian development and cancer metastasis. Our current efforts explore two key issues in the field. First, we will determine the mechanisms by which cells link cell-cell junction to the actomyosin cytoskeleton to allow cell shape change without disrupting epithelial integrity. We hypothesize that cells use different linkers and junctional architectures to drive different key cell shape change or migratory events. Second, we will build on the existing knowledge of the biochemical functions of individual actin regulators to define how cells integrate these to create the diverse actin structures required during normal development, and how upstream signaling pathways shape this integration. In our second project, we explore how cells choose and maintain fate, using Wnt signaling as a model. Wnt signaling shapes virtually every organ system, plays a key role in homeostasis in many tissues, and is inappropriately activated in several common forms of cancer, including colon cancer, the second leading cause of cancer deaths. In the past ten years we focused on the tumor suppressor Adenomatous polyposis coli (APC), a key negative regulator of the Wnt signaling that is mutated in 80% of all colon cancers. APC also plays Wnt- independent roles in regulating the cytoskeleton, thus facilitating high-fidelity chromosome segregation, which is also disrupted in cancer. Our long-term goal is to determine how APC and its protein partners regulate both Wnt signaling and the cytoskeleton during normal development and homeostasis, and how that goes wrong in cancer. In the next funding period we will address two key questions in the field. First, we will define the mechanisms by which the multiprotein destruction complex targets the Wnt effector ß-catenin for phosphorylation, transfers it to an E3 ligase for ultimate proteasomal destruction, and how Wnt signals regulate its activity. This is a paradigm for how regulated protein stability regulates cell signaling. Second, we will explore the regulation of genome stability, defining how APC acts as a cytoskeletal regulator to ensure mitotic fidelity, and defining mechanisms that buffer its loss. More broadly, we will determine how the genetic circuitry of mitotic regulation and checkpoints is re-drawn in different tissues to meet different needs, contrasting epithelial cells and neural progenitors, using our newly developed Drosophila model of microcephaly.

 描述（由适用提供）：在过去的23年中，我们的实验室集中在生物学的一个中心问题上 - 单细胞zygote会自我组装成动物的复杂身体计划？从ß-蛋白酶在细胞粘附和Wnt信号传导中的双重功能开始，我们将研究集中在两个不同的领域。在我们的第一个项目中，我们探讨了细胞在形态发生过程中如何利用细胞 - 细胞相互作用来改变形状，移动和组装偏振组织，并在组织稳态期间维持它们，以及如何在复杂的肌动蛋白调节工具包中整合不同的工具以创建潜水肌动蛋白结构。我们使用高度多学科的方法在果蝇中探讨了这一点，并最近扩展到包括培养的哺乳动物细胞的平行研究。我们关注的蛋白质在哺乳动物发育和癌症转移中起关键作用。我们目前的努力探讨了该领域的两个关键问题。首先，我们将确定细胞将细胞 - 细胞连接连接到肌动蛋白细胞骨架的机制，以允许细胞形状变化而不会破坏上皮完整性。我们假设单元格使用不同的接头和连接架构来驱动不同的键 细胞形状变化或迁移事件。其次，我们将基于对单个肌动蛋白调节剂的生化功能的现有知识，以定义细胞如何整合它们以创建正常开发过程中所需的不同肌动蛋白结构，以及上游信号通路如何塑造这种整合。在我们的第二个项目中，我们使用Wnt信号作为模型来探讨细胞如何选择和维持命运。 Wnt信号几乎塑造了每个器官系统，在许多组织中的体内平衡中都起着关键作用，并且在包括结肠癌在内的几种常见形式的癌症中被不当激活，包括结肠癌，这是癌症死亡的第二大主要原因。在过去的十年中，我们专注于肿瘤抑制腺瘤性息肉大肠杆菌（APC），这是Wnt信号的关键负调节剂，在所有结肠癌的80％中都突变。 APC还在控制细胞骨架方面扮演着独立的角色，从而支持高保真染色体隔离，这在癌症中也受到破坏。我们的长期目标是确定APC及其蛋白质伙伴如何调节正常发育和稳态期间Wnt信号传导和细胞骨架，以及癌症中的错误。在下一个资金期间，我们将解决该领域的两个关键问题。首先，我们将定义多蛋白破坏复合物靶向Wnt效应子 - 钙蛋白以进行磷酸化的机制，将其转移到E3连接酶以实现最终的蛋白酶体破坏，以及Wnt信号如何调节其活性。这是调节蛋白质稳定性如何调节的范式 细胞信号传导。其次，我们将探讨基因组稳定性的调节，定义APC如何充当细胞骨架调节剂，以确保有丝分裂的保真度，并定义缓解其损失的机制。更广泛地说，我们将使用我们新开发的小头畸形果蝇模型来确定如何在不同需求中重新划出有丝分裂调节和检查点的遗传回路。