Analysis of novel pathways for nuclear migration.

核迁移新途径的分析。

• 批准号: 8676464
• 负责人: Shaun P. Murphy
• 金额: $ 1.74万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676464
• 关键词: Actins; Anus; Architecture; Ataxia; Back; Biological Models; Caenorhabditis elegans; Cell Death; Cell Lineage; Cell Nucleus; Cell division; Cell physiology; Cells; Collaborations; Cytoplasmic Protein; Cytoskeleton; Defect; Development; Developmental Cell Biology; Developmental Process; Disease; Emu species; Enhancers; Event; Failure; Fertilization; Fostering; Genes; Genetic; Genetic Screening; Goals; Health; Homologous Gene; Hour; Human; Image; Immigration; Laboratories; Lead; Lesion; Life; Link; Malignant Neoplasms; Mediating; Meiosis; Microfilaments; Microscopy; Microtubules; Mission; Modeling; Molecular; Molecular Genetics; Motor; Movement; Mus; Muscle; Muscle Development; Muscular Dystrophies; Mutation; Neurons; Nuclear; Nuclear Envelope; Organelles; Organism; Pathogenesis; Pathway interactions; Pattern; Phenotype; Positioning Attribute; Process; Progeria; Proteins; Public Health; Research; Retina; Role; Shapes; Signal Transduction; Staging; Structure; System; Temperature; Testing; Transgenic Organisms; United States National Institutes of Health; Work; base; body system; cell growth regulation; cell motility; cell type; cellular imaging; disease-causing mutation; egg; filamin; forward genetics; gene function; genome sequencing; human disease; human tissue; in vivo; innovation; insight; lissencephaly; malformation; member; migration; molecular phenotype; mutant; novel; public health relevance; research study; therapeutic target

DESCRIPTION (provided by applicant): Nuclear migration and positioning are fundamental processes required for proper development, cell polarization, fertilization, cell motility, meiosis and fertilization, as well as cell division. An understanding from a molecular and genetic perspective of how nuclear migration and positioning are accomplished will lead to greater insight into cellular organelle positioning in general, as well as potential therapeutic targets fo a number of heritable human diseases. The experiments proposed here are expected to lead to the discovery and characterization of novel pathways that function parallel to the SUN (UNC-84) and KASH (UNC-83) nuclear-envelope bridge that moves nuclei. I will undertake genetic and cellular approaches to analyze the phenotypes and molecular identities of emu (for the enhancer of the nuclear migration defect of unc-83/84) mutants. One emu gene (fln-2) was identified as a divergent filamin A homolog. Filamins are conserved cytoplasmic proteins that organize the actin cytoskeleton and are involved in diverse cellular processes including cell signaling and mechanotransduction, regulation of cellular architecture, and have recently been shown to regulate nuclear shape in cultured mouse cells. In humans, heritable diseases caused by mutations in filamin genes lead to various diseases of the major organ systems. The overall central hypothesis of this proposal is to characterize novel pathways required for nuclear migration using the model system C. elegans. In order to accomplish this, a combination of forward genetics and whole genome sequencing will be used to identify the molecular basis of the lesions in the emu candidates. To more fully understand emu nuclear migration defects, a live cell imaging system will be developed, which is expected to advance our understanding of nuclear migration in a developing organism. As an example of an analysis of the cellular role of an emu gene, the cellular roles of FLN-2 during P-cell nuclear migration will be examined. The proposed study is innovative and significant because of the strengths of our model system. Most importantly, the results are expected to determine how emu genes function in nuclear migration in the context of a living organism. These results will significantly advance the field by elucidating novel pathways required for nuclear migration. The proposed activities will lead to a better understanding of how nuclear migration is accomplished at the cellular and molecular levels and potentially shed mechanistic insights into the pathogenesis of heritable diseases caused by mutations in genes required for nuclear migration and positioning.

描述(申请人提供)：细胞核迁移和定位是正常发育、细胞极化、受精、细胞运动、减数分裂所必需的基本过程。 受精，以及细胞分裂。从分子和遗传学的角度理解细胞核迁移和定位是如何完成的，将有助于更深入地了解细胞器的总体定位，以及一些可遗传人类疾病的潜在治疗靶点。这里提出的实验有望导致发现和描述与太阳(UNC-84)和KASH(UNC-83)平行运行的新路径-移动原子核的核包膜桥。我将采用遗传和细胞方法来分析emu(针对UNC-83/84核迁移缺陷的增强子)突变体的表型和分子特性。一个emu基因(fln-2)被鉴定为发散型细丝蛋白A同源物。丝蛋白是一种保守的细胞质蛋白，它组织肌动蛋白的细胞骨架，参与多种细胞过程，包括细胞信号和机械转导，细胞结构的调节，最近被证明在培养的小鼠细胞中调节细胞核的形状。在人类中，由丝蛋白基因突变引起的可遗传疾病会导致主要器官系统的各种疾病。这一提议的总体中心假设是利用线虫模型系统描述核迁移所需的新路径。为了实现这一点，将结合正向遗传学和全基因组测序来确定候选EMU患者病变的分子基础。为了更全面地了解EMU的核迁移缺陷，将开发一种活细胞成像系统，有望促进我们对发育中的有机体中核迁移的理解。作为分析emu基因的细胞作用的一个例子，我们将研究Fln-2在P细胞核迁移过程中的细胞作用。由于我们的模型系统的优势，建议的研究具有创新性和重要意义。最重要的是，这些结果有望确定在活的有机体背景下，emu基因如何在核迁移中发挥作用。这些结果将通过阐明核迁移所需的新途径大大推动这一领域的发展。拟议的活动将导致更好地理解核迁移是如何在细胞和分子水平上完成的，并可能对核迁移和定位所需基因突变引起的可遗传疾病的发病机制提供机械性见解。