Engineering external forces for manipulating cargo transport in live neurons

设计外力来操纵活神经元中的货物运输

基本信息

批准号：
8358351
负责人：
Bianxiao Cui
金额：
$ 235.5万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2017-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (Provided by the applicant) Abstract: The axon acts as a conduit for organized transport of materials between the cell body and the synapse, a process that is essential for the function and survival of neurons. Defective axonal transport, such as accumulation of axonal cargoes, has been linked with a range of neurodegenerative diseases by extensive genetic and biochemical studies. However, it is still unclear whether and how defective axonal transport might play a role in the progression of neuronal degeneration. Genetic and biochemical approaches lack precise control over when and where the cargo accumulations will happen along the axon, which makes it difficult to pinpoint the role of ""transport defect"" in the process of neuronal degeneration. In this proposal, we propose to engineer magnetic and optical forces that specifically stall a population of axonal cargoes that contain magnetic or optical nanoparticle probes at the trapping area. Physically stalling the cargoes would be one of the most direct means to perturb a cargo transport process, which, however, are technically challenging in live cells. We will overcome those challenges using advanced nanofabrication, imaging techniques and novel nanoparticle probes. Inside the narrow axon, stalled cargoes will act as roadblocks to slow down the trafficking of other probe-free cargoes that are not affected by external forces. Such force-induced traffic jams afford new approaches to investigate whether blocking the axonal transport is sufficient to induce neuronal degeneration and how cellular processes response to axonal traffic blockage. Public Health Relevance: Age-related neurodegenerative diseases, such as Alzheimer's disease, impact the lives of millions and pose a growing public health challenge. This study aims to investigate how defective axonal transport might cause or contribute to the progression of those neurodegenerative diseases. The findings of this research will advance our understanding of age-related neuronal death and assist therapeutic interventions for the treatment of these disorders.

描述（申请人提供）摘要：轴突充当细胞体和突触之间材料运输的管道，这对于神经元的功能和存活至关重要。有缺陷的轴突运输，例如轴突货物的积累，已通过广泛的遗传和生化研究与一系列神经退行性疾病联系在一起。但是，尚不清楚轴突转运是否以及如何在神经元变性的进展中起作用。遗传和生化方法无法精确控制货物沿轴突何时何地发生货物的积累，这使得很难确定“转运缺陷”在神经元变性过程中的作用。在此提案中，我们建议设计磁性和光学力，这些磁力和光学力专门停滞了捕获区域的轴突货物种群，这些轴突货物中包含磁性或光学纳米粒子探针。物理上停滞的货物将是扰动货物运输过程的最直接手段之一，但是，在技术上，在实时细胞中，这在技术上具有挑战性。我们将使用先进的纳米化，成像技术和新型纳米颗粒探针克服这些挑战。在狭窄的轴突内部，停滞的货物将充当障碍，以减慢其他不受外部力量影响的其他无探测器货物的贩运。这种力引起的交通拥堵提供了新的方法来研究阻断轴突运输是否足以诱导神经元变性以及细胞过程如何对轴突交通堵塞的响应。公共卫生相关性：与年龄有关的神经退行性疾病，例如阿尔茨海默氏病，影响了数百万的生活，并构成了日益增长的公共卫生挑战。这项研究旨在研究轴突运输有缺陷可能导致或导致这些神经退行性疾病的发展。这项研究的结果将提高我们对与年龄相关的神经元死亡的理解，并帮助治疗这些疾病的治疗干预措施。