Centrosome Mis-Regulation and Blood Vessel Function

中心体失调与血管功能

• 批准号: 8418818
• 负责人: Victoria L Bautch
• 金额: $ 36.18万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8418818
• 关键词: 3-Dimensional; Address; Affect; Aneuploidy; Angiogenic Factor; Area; Behavior; Behavioral Genetics; Biological Assay; Blood Vessels; Cell Cycle; Cell Survival; Cell division; Cell physiology; Cells; Centrosome; Chromosomal Instability; Chromosome Segregation; Chromosomes; Complement; Cyclin E; Cytoskeleton; Data; Defect; Development; Disease model; Endothelial Cells; Environment; Frequencies; Functional disorder; Genetic; Genetic Materials; Goals; Grant; Hypoxia; Image; In Situ; Interphase; Lead; Life; Link; MEKs; Malignant Neoplasms; Mediating; Microtubule-Organizing Center; Microtubules; Mitosis; Mitotic; Modeling; Morphogenesis; Mus; Mutation; Outcome; Output; Pathway interactions; Phenocopy; Phosphoric Monoester Hydrolases; Phosphotransferases; Predisposition; Primary Neoplasm; Publishing; Regulation; Reporter; Resolution; Signal Transduction; Testing; Time; Tissues; Transgenic Mice; Vascular Endothelial Growth Factors; Work; base; cell behavior; daughter cell; embryonic stem cell; genetic manipulation; human CCNE1 protein; in vivo; in vivo Model; innovation; neoplastic cell; novel; public health relevance; research study; response; retina blood vessel structure; therapeutic target; tool; tumor

DESCRIPTION (provided by applicant): Centrosomes nucleate microtubules in cells, and organize them via a microtubule organizing center (MTOC) during interphase and via spindles during mitosis. Centrosome duplication is normally tightly regulated to occur once and only once per cell cycle, and loss of this regulation leads to excess centrosomes, genetic instability, and aneuploidy in tumor cells. We recently showed, for the first time, that endothelial cells (EC) in blood vessels exposed to elevated VEGF-A signaling have excess centrosomes, mediated through Akt, MEK/ERK, and Cdk2/cyclin E. Centrosome excess is predicted to perturb the cytoskeleton and result in alterations in cellular behaviors, although this link has not been made in cells or tissues; it also is predicted to produce chromosome instability and aneuploidy, leading to EC with profound changes from the norm. This work will test the hypothesis that excess centrosomes in EC perturb vessel function via both mitotic and non-mitotic perturbations, and examine the mechanisms that lead to centrosome mis-regulation upon angiogenic factor stimulation. This highly innovative hypothesis will be tested with three aims that address the questions: 1) What are the inputs and mechanisms that lead to EC centrosome mis- regulation? 2) What are the consequences of excess centrosomes to EC behaviors and sprouting? and 3) what are the outcomes of excess centrosomes in EC of vessels in vivo? We will utilize cell- based models of blood vessel formation and in vivo mouse developmental and disease models to address the questions. The significance of this work will be to reveal susceptibility in developing vessels for centrosome-mediated EC dysfunction and genetic instability, which is predicted to contribute to blood vessel dysfunction in novel ways, and lead to new and distinct therapeutic targets.

描述（由申请人提供）：中心体在细胞中的微管成核，并通过微管组织中心（MTOC）在相间和有丝分裂过程中通过纺锤体组织它们。通常会严格严格调节中心体重复，每个细胞周期一次仅发生一次，而这种调节的丢失会导致肿瘤细胞中过量的中心体，遗传不稳定性和非整倍性。最近，我们首次表明，暴露于VEGF-A信号升高的血管中的内皮细胞（EC）具有过量的中心体，通过AKT，MEK/ERK和CDK2/Cyclin E.中心体的过量介导，预计会使细胞骨架和细胞行为的危害，但导致细胞的障碍或组织的障碍。还可以预测它会产生染色体不稳定性和非整倍性，领先 向EC带来了与规范的深刻变化。这项工作将检验以下假设：EC扰动血管中的过量中心体通过有丝分裂和非有丝分裂扰动的功能，并检查导致血管生成因子刺激的中心体不良调节的机制。这一高度创新的假设将通过三个目的进行测试，以解决以下问题：1）导致EC中心体和调节的输入和机制是什么？ 2）多余的中心体对EC行为和发芽有何影响？ 3）体内血管EC中过量的中心体的结果是什么？我们将利用基于细胞的血管形成和体内小鼠发育和疾病模型的模型来解决这些问题。这项工作的意义将是揭示在开发中心体介导的EC功能障碍和遗传不稳定性的血管中的敏感性，这预计将在新颖的方式中导致血管功能障碍，并导致新的和独特的治疗靶标。