Regulation of Coordination of Molecular Motors

分子马达协调的调节

• 批准号: 7999994
• 负责人: Vladimir I Gelfand
• 金额: $ 10.68万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-14 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7999994
• 关键词: ATP Hydrolysis; Actin-Binding Protein; Actins; Address; Affect; Binding; Biological Models; Cell division; Cells; Chemicals; Coupling; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytoplasm; Data; Defect; Diffusion; Drosophila genus; Drosophila melanogaster; Dynein ATPase; Eukaryotic Cell; Goals; Image; In Vitro; Intermediate Filaments; Interphase; Kinesin; Latex Bead; Libraries; Life; Link; Macromolecular Complexes; Magnetism; Measures; Mediating; Melanophores; Melanosomes; Messenger RNA; Microfilaments; Microtubules; Molecular; Molecular Motors; Monitor; Motor; Motor Neurons; Movement; Mutate; Myosin ATPase; Neurodegenerative Disorders; Neurofibromatoses; Neurons; Normal Cell; Optics; Organelles; Pathway interactions; Phagocytes; Phagosomes; Phosphotransferases; Pigmentation physiologic function; Pigments; Positioning Attribute; Process; Proteins; RNA Interference; Rana; Regulation; Research Personnel; Resolution; Role; Signal Transduction; Signaling Molecule; Slide; Source; Surface; System; Systems Analysis; Testing; Time; Tubulin; Vimentin; Viscosity; Work; Xenopus; Xenopus laevis; cell motility; design; feeding; in vivo; knock-down; laser tweezer; millisecond; motor control; mutant; organelle movement; overexpression; particle; permanent cell line; photoactivation; programs; protein complex; research study

DESCRIPTION (provided by applicant): Transport of organelles and macromolecular complexes through the cytoplasm is essential for every eukaryotic cell. This process is performed by motor proteins that use the chemical energy of ATP hydrolysis to move their cargo along microtubules and actin filaments. The spatial and temporal control of motor- dependent transport is critical for cell division, organelle transport and positioning, and the movement of mRNA and protein complexes within the cell. Defects in organelle transport and motor-associated proteins contribute or cause many neurodegenerative diseases, neurofibromatosis and defects of pigmentation. The goal of this proposal is to understand how multiple motors moving a cargo function together to achieve targeted and timely delivery of components in the cell. We want to know how the activity of multiple motors is coordinated in a cell and how these motors are regulated. Two biological models will be used for the proposed work. A permanent cell line of pigment cells (melanophores) from the frog Xenopus laevis will be used to study the regulation of movement. This is an ideal system for the analysis of regulation because the motors are well-characterized and movement of pigment organelles can be triggered by changes in cAMP concentration. Cultured neuronal and phagocytic cells from Drosophila melanogaster are extremely sensitive to protein knock-down by RNAi allowing for efficient functional analysis of components involved in motility and coordination of motors. This proposal has four specific aims: (i) to find the mechanisms of cross-talk between microtubule motors of the opposite polarity; (ii) to find if multiple motors of the same polarity make transport more efficient and determine to what extent movement of the microtubules contributes to cargo transport; (iii) to find how myosin motors, moving along a network of actin filaments, and intermediate filaments interacting with cargo, modulate long-range transport by microtubule motors; (iv) to find mechanisms of targeting signaling molecules to cargo organelles and the identity of components downstream of signaling molecules.

描述（由申请人提供）：细胞器和大分子复合物通过细胞质的运输对于每个真核细胞都是必需的。该过程由运动蛋白执行，运动蛋白利用 ATP 水解的化学能沿着微管和肌动蛋白丝移动其货物。运动依赖性运输的空间和时间控制对于细胞分裂、细胞器运输和定位以及细胞内 mRNA 和蛋白质复合物的运动至关重要。细胞器运输和运动相关蛋白的缺陷导致或导致许多神经退行性疾病、神经纤维瘤病和色素沉着缺陷。该提案的目标是了解多个电机如何共同移动货物，以实现单元内组件的有针对性和及时的交付。我们想知道细胞中多个马达的活动是如何协调的以及这些马达是如何被调节的。两个生物模型将用于拟议的工作。来自非洲爪蟾的色素细胞（黑色素细胞）的永久细胞系将用于研究运动调节。这是用于分析调节的理想系统，因为电机具有良好的特性，并且色素细胞器的运动可以通过 cAMP 浓度的变化触发。培养的黑腹果蝇神经元和吞噬细胞对 RNAi 导致的蛋白质敲除极其敏感，从而可以对参与运动和运动协调的成分进行有效的功能分析。该提案有四个具体目标：（i）找到相反极性的微管马达之间的串扰机制； (ii) 找出相同极性的多个马达是否使运输更加有效，并确定微管的运动在多大程度上有助于货物运输； (iii) 找出肌球蛋白马达沿着肌动蛋白丝网络移动，以及与货物相互作用的中间丝，如何通过微管马达调节长距离运输； (iv) 寻找将信号分子靶向货物细胞器的机制以及信号分子下游成分的身份。