GLUT4囊泡的量子点标记及其在活细胞内纳米级实时定位研究
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摘要
葡萄糖转运蛋白GLUT4在肌肉细胞和脂肪细胞的葡萄糖摄取过程中起着关键作用,对维持体内葡萄糖的动态平衡至关重要。GLUT4在细胞内的循环过程涉及到细胞胞吐和胞吞活动的许多分子机制。深入研究GLUT4囊泡在胞内转运的完整动态过程,有助于进一步揭示GLUT4的转位机制和胞内大分子跨膜转运的基本生命现像。但是,由于三维单微粒跟踪技术的局限,只能观察GLUT4囊泡在胞内转运的某些短时程和局部区域的过程,这导致与GLUT4囊泡胞内转运过程相关的许多重要科学问题还没有得到解答。本文结合了新的纳米级三维单微粒跟踪技术和量子点标记技术,为全细胞范围内GLUT4囊泡转运机制研究提供了高精度、长时程的实时监测及分析平台。
本文主要完成了以下几个方面的工作：
1)将量子点标记技术引入到纳米级三维单微粒跟踪研究领域。设计了用量子点标记葡萄糖转运蛋白囊泡的实验流程,证明了这种标记方法的灵敏性、特异性、无毒性。实验结果表明,与传统的荧光染料相比,量子点因其光物理特性,在全细胞范围内GLUT4囊泡胞内转运过程研究中具有某些优越性。为解决三维纳米级跟踪中图像信噪比低、目标分割难、跟踪时程短、空间分辨率低等问题提供了新的思路。
2)对单微粒的三维纳米级定位算法进行了研究。考虑到实时性和分辨率的要求,本文重点研究了宽场显微镜荧光图像的离焦图像和离焦距离的关系,得出了二者的关系公式,从原理上为自校正离焦定位系统的设计奠定了基础。
3)设计和构建了自校正离焦定位系统。搭建了进行三维纳米级跟踪的硬件和软件基本平台。设计了一套能对Z轴位移进行精确控制的压电晶体纳米级微位移控制器。对TILLVision成像系统软件进行了改造,在原有的成像系统软件中加入了三维纳米级离焦定位算法。
本文所建立的有关GLUT4囊泡三维纳米级实时定位的新方法和新的实验系统,亦可应用于内分泌细胞和神经细胞分泌机制研究以及蛋白质跨膜转运研究等前沿科学领域。进一步发展,有可能在一定条件下实现对活体细胞内蛋白质大分子的三维纳米级实时定位和跟踪。
Glut4 (Glucose Transporter 4), which plays a key role in insulin uptake in muscle and fat cells, is essential for maintaining whole body glucose homeostasis. The recycling of GLUT4 between the intracellular compartments and the cell surface involves many molecular mechanisms of endocytosis and exocytosis. A further investigation in GLUT4 translocation is helpful for revealing the basic life phenomenon of the across-membrane transport of macromolecules in live cells. However, only some short-term processes of GLUT4 translocation in partial aereas of the cell could be observed because of the limitations of the current 3D single particle tracking technique. This results that lots of important scientific problems on GLUT4 translocation can not be solved yet. By combining the new 3D single particle positioning technique with nano-precision with the quantum dots labeling technique, this study provides a platform suitable for long-term, real time mornitoring and analying on the GLUT4 trafficking in whole cell.
The main works of this thesis are presented as follows:
1. Quantum dots were introduced into the research of single particle tracking as an alternative to conventional dyes. A special protocol was developed to label GLUT4 in L6 cells and was demonstrated to be sensitive, specific, nontoxic. The results indicate that, compared with conventional dyes, quantum dots are advantageous in the research of 3D single particle positioning due to their unique optical and spectroscopic properties. Some difficult problems in 3D single particle positioning, such as low spacial resolution, low signal noise ratio, difficulties in object segmentation, short tracking time duration, have been solved by this method.
2. Algorithms for 3D single particle positioning were investgated. Considering the request of real time and spatial resolution, we put the emphsis on investigating the relationship between the off-focus image and the off-focus distance. An approximately formula between the diameter of the outmost ring and the off-focus distance in Z-axis of single particle was established, which provided solid theory basis for real-time 3D single particle positioning with nano precision.
3. A self-adjustable off-focus positioning system, including hardware and software platforms, was designed and established to perform real-time 3D single particle tracking. A piezocrystal mirco-displacement controller was designed to control the movement of object lens in Z-axis precisely. The Algorithm of real-time 3D single particle tracking was inserted to the software of TILLVision imaging system to meet the needs for real-time image acquisition and processing.
The new method and experiment system of 3D single particle positioning established in this thesis can also be used in frontier science areas such as secretion mechanism of endocrine and neron cells, across-membrane transport of protein. With further development, this method has the potential of positioning and tracking protein macromolecules in live cells in real time and 3D.
本文主要完成了以下几个方面的工作：
1)将量子点标记技术引入到纳米级三维单微粒跟踪研究领域。设计了用量子点标记葡萄糖转运蛋白囊泡的实验流程,证明了这种标记方法的灵敏性、特异性、无毒性。实验结果表明,与传统的荧光染料相比,量子点因其光物理特性,在全细胞范围内GLUT4囊泡胞内转运过程研究中具有某些优越性。为解决三维纳米级跟踪中图像信噪比低、目标分割难、跟踪时程短、空间分辨率低等问题提供了新的思路。
2)对单微粒的三维纳米级定位算法进行了研究。考虑到实时性和分辨率的要求,本文重点研究了宽场显微镜荧光图像的离焦图像和离焦距离的关系,得出了二者的关系公式,从原理上为自校正离焦定位系统的设计奠定了基础。
3)设计和构建了自校正离焦定位系统。搭建了进行三维纳米级跟踪的硬件和软件基本平台。设计了一套能对Z轴位移进行精确控制的压电晶体纳米级微位移控制器。对TILLVision成像系统软件进行了改造,在原有的成像系统软件中加入了三维纳米级离焦定位算法。
本文所建立的有关GLUT4囊泡三维纳米级实时定位的新方法和新的实验系统,亦可应用于内分泌细胞和神经细胞分泌机制研究以及蛋白质跨膜转运研究等前沿科学领域。进一步发展,有可能在一定条件下实现对活体细胞内蛋白质大分子的三维纳米级实时定位和跟踪。
Glut4 (Glucose Transporter 4), which plays a key role in insulin uptake in muscle and fat cells, is essential for maintaining whole body glucose homeostasis. The recycling of GLUT4 between the intracellular compartments and the cell surface involves many molecular mechanisms of endocytosis and exocytosis. A further investigation in GLUT4 translocation is helpful for revealing the basic life phenomenon of the across-membrane transport of macromolecules in live cells. However, only some short-term processes of GLUT4 translocation in partial aereas of the cell could be observed because of the limitations of the current 3D single particle tracking technique. This results that lots of important scientific problems on GLUT4 translocation can not be solved yet. By combining the new 3D single particle positioning technique with nano-precision with the quantum dots labeling technique, this study provides a platform suitable for long-term, real time mornitoring and analying on the GLUT4 trafficking in whole cell.
The main works of this thesis are presented as follows:
1. Quantum dots were introduced into the research of single particle tracking as an alternative to conventional dyes. A special protocol was developed to label GLUT4 in L6 cells and was demonstrated to be sensitive, specific, nontoxic. The results indicate that, compared with conventional dyes, quantum dots are advantageous in the research of 3D single particle positioning due to their unique optical and spectroscopic properties. Some difficult problems in 3D single particle positioning, such as low spacial resolution, low signal noise ratio, difficulties in object segmentation, short tracking time duration, have been solved by this method.
2. Algorithms for 3D single particle positioning were investgated. Considering the request of real time and spatial resolution, we put the emphsis on investigating the relationship between the off-focus image and the off-focus distance. An approximately formula between the diameter of the outmost ring and the off-focus distance in Z-axis of single particle was established, which provided solid theory basis for real-time 3D single particle positioning with nano precision.
3. A self-adjustable off-focus positioning system, including hardware and software platforms, was designed and established to perform real-time 3D single particle tracking. A piezocrystal mirco-displacement controller was designed to control the movement of object lens in Z-axis precisely. The Algorithm of real-time 3D single particle tracking was inserted to the software of TILLVision imaging system to meet the needs for real-time image acquisition and processing.
The new method and experiment system of 3D single particle positioning established in this thesis can also be used in frontier science areas such as secretion mechanism of endocrine and neron cells, across-membrane transport of protein. With further development, this method has the potential of positioning and tracking protein macromolecules in live cells in real time and 3D.
引文
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