IR-LAMP: Optigenetic technology to spatially manipulate protein function in vivo

IR-LAMP:光遗传学技术在体内空间操纵蛋白质功能

基本信息

  • 批准号:
    8146668
  • 负责人:
  • 金额:
    $ 240万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-09-30 至 2016-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (Provided by the applicant) Abstract: Major advances in the biological sciences are coupled to technological innovation. Here, I propose to develop IR-LAMP (IR Laser-Assisted Modulation of Proteins), a novel optigenetic technology using an infrared laser to manipulate protein function at specific sub-cellular locations with precise temporal resolution to probe fundamental questions in biology. Complex cellular behaviors, such as cell division or neuronal transmission, require a high degree of molecular regulation at a sub-cellular level. Much of the molecular machinery active during individual cell behaviors, however, is also required in other essential events, thus precluding the study of future events (e.g. during gamete production vs. morphogenesis). This limitation has been partially overcome by conditional, temperature- sensitive genetics; however, even the best temperature-controlled environment restricts ts protein inactivation spatially to a cellular or organism level. This technical limitation prevents us from determining the specific sub-cellular structure at which a given molecular pathway functions. To overcome these challenges, I will develop IR-LAMP technology using an infrared laser to target specific sub-cellular locations and inactivate fast-acting ts alleles in embryos from the nematode Caenorhabditis elegans with high temporal and spatial resolution. With intensive screening, I have obtained a bank of temperature sensitive mutations in the molecular machinery required for the highly spatially regulated process of cytokinesis. Cytokinesis is the last stage of cell division, when a mother cell is physically divided into two daughter cells. Using IR-LAMP and my collection of fast-acting temperature-sensitive mutants, I will locally inactivate the core molecular machinery required for cytokinesis in distinct sub-cellular compartments and determine the contributing functional compartments for a given essential molecular complex (e.g. at the central spindle vs. the contractile ring). I will also screen for fast-acting cold-sensitive mutations to locally activate protein function with the same spatial and temporal resolution. Once developed, IR-LAMP technology will be applicable to any complex cell behavior accessible by light microscopy--a virtually endless list of cell or developmental processes, such as studies on cell adhesion, polarity establishment, cell migration, or cell-cell signaling. Public Health Relevance: Scientific frontiers are advanced by the development of new technology; the development of IR-LAMP will open the doors for basic research aimed at probing the spatial regulation of molecular function in vivo. Further, as infrared lasers can penetrate deep into tissues, IRLAMP could also be adopted for use in humans to treat localized diseases, such as cancer, using transgenic stem cells or nanoparticles containing thermally sensitive proteins. For example, nanoparticles coupled to a thermally sensitive pro-apoptotic protein could be locally activated in cancer stem cells with IR-LAMP to induce cell death and stop tumor growth.
描述(由申请人提供) 翻译后摘要:在生物科学的重大进展,加上技术创新。在这里,我建议开发IR-LAMP(红外激光辅助蛋白质调制),这是一种新型的光学遗传技术,使用红外激光在特定的亚细胞位置操纵蛋白质功能,具有精确的时间分辨率,以探索生物学中的基本问题。 复杂的细胞行为,如细胞分裂或神经元传递,需要在亚细胞水平上进行高度的分子调控。然而,在个体细胞行为期间活跃的大部分分子机制在其他基本事件中也是必需的,因此排除了对未来事件的研究(例如在配子产生与形态发生期间)。这种限制已被条件性的温度敏感性遗传学部分克服;然而,即使是最好的温度控制环境也将ts蛋白失活空间限制在细胞或生物体水平。这种技术限制使我们无法确定特定的亚细胞结构,在该结构下,给定的分子途径发挥作用。 为了克服这些挑战,我将开发IR-LAMP技术,使用红外激光器以高时间和空间分辨率靶向线虫线虫胚胎中的特定亚细胞位置和快速作用ts等位基因。通过密集的筛选,我已经获得了一个温度敏感的突变库,这些突变存在于胞质分裂高度空间调控过程所需的分子机制中。胞质分裂是细胞分裂的最后阶段,此时母细胞在物理上分裂为两个子细胞。使用IR-LAMP和我收集的快速作用的温度敏感突变体,我将在不同的亚细胞隔室中局部地定位胞质分裂所需的核心分子机制,并确定给定的基本分子复合物的贡献功能隔室(例如,在中央纺锤体与收缩环)。我还将筛选快速作用的冷敏感突变,以相同的空间和时间分辨率局部激活蛋白质功能。 一旦开发出来,IR-LAMP技术将适用于光学显微镜可访问的任何复杂细胞行为-细胞或发育过程的几乎无穷无尽的列表,例如对细胞粘附,极性建立,细胞迁移或细胞间信号传导的研究。 公共卫生相关性:新技术的发展推动了科学前沿; IR-LAMP的发展将为旨在探索体内分子功能空间调控的基础研究打开大门。此外,由于红外激光可以深入组织,IRLAMP也可以用于人类,使用转基因干细胞或含有热敏蛋白的纳米颗粒治疗局部疾病,如癌症。例如,与热敏促凋亡蛋白偶联的纳米颗粒可以用IR-LAMP在癌症干细胞中局部活化,以诱导细胞死亡并阻止肿瘤生长。

项目成果

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专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)

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JULIE C CANMAN其他文献

JULIE C CANMAN的其他文献

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{{ truncateString('JULIE C CANMAN', 18)}}的其他基金

Probing the spatiotemporal regulation of cell division
探讨细胞分裂的时空调控
  • 批准号:
    10456882
  • 财政年份:
    2019
  • 资助金额:
    $ 240万
  • 项目类别:
Probing the spatiotemporal regulation of cell division
探讨细胞分裂的时空调控
  • 批准号:
    10019573
  • 财政年份:
    2019
  • 资助金额:
    $ 240万
  • 项目类别:
Probing the spatiotemporal regulation of cell division
探讨细胞分裂的时空调控
  • 批准号:
    10220996
  • 财政年份:
    2019
  • 资助金额:
    $ 240万
  • 项目类别:
Cell type-variation of cytokinesis
细胞类型-胞质分裂的变异
  • 批准号:
    10569620
  • 财政年份:
    2016
  • 资助金额:
    $ 240万
  • 项目类别:
Cell Polarity and Cytokinesis
细胞极性和细胞分裂
  • 批准号:
    9010016
  • 财政年份:
    2016
  • 资助金额:
    $ 240万
  • 项目类别:
Cell type-variation of cytokinesis
细胞类型-胞质分裂的变异
  • 批准号:
    9973404
  • 财政年份:
    2016
  • 资助金额:
    $ 240万
  • 项目类别:

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