Regulation of Microtubule-based Membrane Traffic by Septin GTPases

描述(申请人提供)：微管细胞骨架为膜细胞器和大分子的运输和定位提供了一个结构框架，对细胞分裂、细胞运动和细胞信号传递是必不可少的。微管依赖的转运障碍是癌症和神经退行性变发生和发展的基础。了解控制MT依赖的运动和MT组织的分子机制对于发展基于MT的治疗干预具有极其重要的意义，其中许多治疗措施正在临床应用。最近，我们发现了一个新的GTP酶家族，称为Septins，它对染色体和膜泡的微管依赖的运输是必不可少的。间隔蛋白与多种癌症和神经退行性疾病有关，包括阿尔茨海默氏症和帕金森氏症。我们研究的长期目标是了解间隔蛋白如何在微管依赖的运动中发挥作用。我们假设，Septins选择性地调节微管与马达和微管相关蛋白(MAP)的相互作用。在这里，我们将确定毛细管蛋白与微管相互作用的分子机制。重要的是，我们将测试Septin如何影响特定马达和MAP的微管结合。我们将利用这一知识来阐明Septin在活上皮细胞和神经元中膜运输的方向性和/或速度中的作用。由于细胞内转运的方向性受到单个微管轨迹的稳定性和取向的影响，我们将研究间隔素如何控制微管的空间组织和稳定性。我们的研究将为微管依赖转运的调控提供新的见解，并为基于Septin的治疗药物(例如抑制肽)的设计提供一个模型，该药物可用作微管靶向药物的替代品。

DESCRIPTION (provided by applicant): The microtubule cytoskeleton provides a structural framework for the transport and positioning of membrane organelles and macromolecules, and is essential for cell division, cell motility and cell signaling. Disruption of microtubule-dependent transport underlies the pathogenesis and progression of cancer and neurodegeneration. Understanding the molecular mechanisms that control MT-dependent motility and MT organization is of paramount significance for the development of MT-based therapeutic interventions, many of which are being clinically applied. Recently, we discovered that a novel family of GTPases termed septins is essential for the microtubule-dependent transport of chromosomes and membrane vesicles. Septins are linked to a diversity of cancers and neurodegenerative diseases including Alzheimer's and Parkinson's. The long-term goal of our research is to understand how septins function in microtubule-dependent motility. We hypothesize that septins selectively modulate the interaction of microtubules with motors and microtubule-associated proteins (MAPs). Here, we will determine the molecular mechanism by which septins interact with microtubules. Importantly, we will test how septins influence the microtubule binding of specific motors and MAPs. We will use this knowledge to elucidate septin roles in the directionality and/or velocity of membrane traffic in live epithelia and neurons. Because the directionality of intracellular transport is influenced by the stability and orientation of individual microtubule tracks, we will examine how septins control the spatial organization and stability of microtubules. Our studies will provide new insights into the regulation of microtubule-dependent transport, and generate a model for the design of septin-based therapeutics (e.g., inhibitory peptides), which can be used as an alternative to microtubule-targeting agents.