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（由申请人提供）：在过去的23年里，我们的实验室一直专注于生物学的中心问题之一-单细胞受精卵如何自我组装成动物的复杂身体计划？从β- catenin在细胞粘附和Wnt信号转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，我们探索细胞如何利用细胞间的相互作用来改变形状，移动，并在形态发生过程中组装极化组织，并在组织稳态过程中保持这些，以及细胞如何在复杂的肌动蛋白调控工具包中整合不同的工具来创建不同的肌动蛋白结构。我们在果蝇中探索这一点，使用高度多学科的方法，最近扩大到包括在培养的哺乳动物细胞中的平行研究。我们关注的蛋白质在哺乳动物发育和癌症转移中起着关键作用。我们目前的努力探讨该领域的两个关键问题。首先，我们将确定细胞将细胞-细胞连接到肌动球蛋白细胞骨架以允许细胞形状改变而不破坏上皮完整性的机制。我们假设细胞使用不同的连接体和连接结构来驱动不同的关键酶， 细胞形状改变或迁移事件。其次，我们将在现有的单个肌动蛋白调节因子生化功能知识的基础上，定义细胞如何整合这些调节因子以创建正常发育期间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，我们探索细胞如何选择和维持命运，使用Wnt信号作为模型。Wnt信号几乎塑造了每一个器官系统，在许多组织的体内平衡中起着关键作用，并且在几种常见的癌症中被不适当地激活，包括结肠癌，这是癌症死亡的第二大原因。在过去的十年中，我们专注于肿瘤抑制剂腺瘤性结肠息肉病（APC），这是Wnt信号传导的关键负调控因子，在80%的结肠癌中发生突变。APC还在调节细胞骨架中发挥Wnt非依赖性作用，从而促进高保真染色体分离，其在癌症中也被破坏。我们的长期目标是确定APC及其蛋白质伴侣如何在正常发育和稳态过程中调节Wnt信号传导和细胞骨架，以及在癌症中如何出错。在下一个供资期，我们将解决这一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β-连环蛋白磷酸化的机制，将其转移到E3连接酶最终蛋白酶体破坏，以及Wnt信号如何调节其活性。这是一个关于蛋白质稳定性如何调节 细胞信号其次，我们将探讨基因组稳定性的调节，定义APC如何作为细胞骨架调节剂，以确保有丝分裂的保真度，并定义缓冲其损失的机制。更广泛地说，我们将确定有丝分裂调控和检查点的遗传电路如何在不同组织中重新绘制以满足不同的需求，对比上皮细胞和神经祖细胞，使用我们新开发的果蝇小头畸形模型。