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Optogenetic Mitochondria-Directed Proteins

光遗传学线粒体定向蛋白

基本信息

批准号：
9113687
负责人：
DAVID S. LAWRENCE
金额：
$ 19万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2017-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The ability to control the biochemistry of cells and organisms with light has elicited widespread attention. However, in spite of the promise that optogenetic tools hold for biology and medicine, their ready application is constrained by protein engineering strategies that are labor intensive and require a level of biochemical and cellular engineering sophistication that is not available in many biology labs. Indeed, although much has been made of the potential of optogenetics, surprisingly few genetically encoded light-responsive proteins have been described. Is it possible to devise an optogenetic protein engineering strategy that is so straightforward that biologists can serve as their own protein engineers? In this regard, we have developed a potentially general strategy that draws its inspiration from the 100-year-old Michaelis Menten equation. This approach has furnished a light-activatable cofilin (light-mediated cell motility) and a light-activatable bax (light-mediate cell death). We will prepare three additional light-responsive proteins in order to explore the scope and limitations of this strategy. The three constructs to be acquired, in conjunction with the two developed to date, are representatives of a large family of proteins known to modulate mitochondrial behavior. Several neurological diseases (Parkinson's, Huntington's, Alzheimer's, and Charcot-Marie-Tooth type 2A) display defects in mitochondrial dynamics, including fusion, fission, transport, and turnover. Recent studies have suggested that it may be possible to ameliorate specific disease phenotypes by altering mitochondrial dynamics. We will explore this premise by examining the ability of the light-responsive proteins under study to modulate mitochondrial behavior in a light-dependent fashion.

描述（由申请人提供）：用光控制细胞和生物体的生物化学的能力引起了广泛的关注。然而，尽管光遗传学工具为生物学和医学带来了希望，但它们的现成应用受到蛋白质工程策略的限制，这些策略是劳动密集型的，并且需要一定程度的生化和细胞工程复杂性，而这是许多生物实验室所不具备的。事实上，尽管人们对光遗传学的潜力进行了很多研究，但令人惊讶的是，对基因编码的光响应蛋白的描述却很少。是否有可能设计出一种简单的光遗传学蛋白质工程策略，让生物学家可以充当自己的蛋白质工程师？在这方面，我们从已有 100 年历史的 Michaelis Menten 方程中汲取灵感，制定了一种潜在的通用策略。这种方法提供了光激活的丝动蛋白（光介导的细胞运动）和光激活的bax（光介导的细胞死亡）。我们将制备三种额外的光响应蛋白，以探索该策略的范围和局限性。即将获得的三个构建体，连同迄今为止开发的两个构建体，是已知调节线粒体行为的一大蛋白质家族的代表。几种神经系统疾病（帕金森病、亨廷顿病、阿尔茨海默病和 2A 型腓骨肌萎缩症）显示线粒体动力学缺陷，包括融合、裂变、运输和周转。最近的研究表明，有可能通过改变线粒体动力学来改善特定的疾病表型。我们将通过检查所研究的光响应蛋白以光依赖性方式调节线粒体行为的能力来探索这一前提。