Array Tomography Hardware and Software Development

描述(申请人提供)：了解大脑的结构和功能是重大的科学问题之一。大脑的神经退行性疾病是代价最高、破坏性最大、治疗效果最差的人类疾病之一，可以说是因为人们对它们没有很好的了解，这排除了理性的治疗方法。阵列断层成像是一种新的组织成像方法，在所有三个维度上的分辨率都足以分辨单个突触，并在1-mm3样本中对多个(目前为36个)分子成分进行定量表征。这意味着现在可以构建神经电路的接线图，由几个1亿到10亿个突触组成，并精确描述分子组成。我们相信，这类信息将使研究人员开始理解神经回路的正确功能，更重要的是，开始了解各种神经退化过程是如何存在和进展的。尽管这一前景很诱人，但自2007年首次发表(Micheva and Smith，2007)以来，阵列断层扫描被用于相对较少的研究中，原因是方法的复杂性和在单个研究人员的实验室中建立它的成本。商业机会是将阵列断层扫描作为一项服务提供给研究社区。我们相信，这是将该方法的力量应用于神经科学、癌症研究以及医学诊断和治疗发展中的问题的最佳方式。为此，在这项提案中，我们试图改进在史密斯实验室开发的程序，以便有可能为学术界和工业界提供阵列断层扫描服务。具体地说，我们建议开发一种单一用途的成像仪器，包括控制软件，使组织切片成像可以增加许多倍。此外，我们建议开发一个图像存储和检索系统，以增强阵列断层扫描的商业应用。 公共卫生相关性：随着人口老龄化，阿尔茨海默氏症和帕金森氏症等神经退行性疾病正变得越来越普遍。由于缺乏提供有关这些疾病进展情况的“全景”信息的技术，开发这些疾病的治疗方法的努力受到了阻碍。我们建议开发一种对大面积大脑区域进行高分辨率显微分析的技术，以更全面地了解这些疾病引起的细胞病理，从而发现更有效的治疗方法。

DESCRIPTION (provided by applicant): Understanding the structure and function of the brain is one of the great scientific problems. Neurodegenerative conditions of the brain are among the most expensive, disruptive, and least well-treated human diseases, arguably because they are not well understood, which precludes a rational approach to treatment. Array Tomography is a new method for tissue imaging with resolution in all three dimensions sufficient to resolve individual synapses and with quantitative characterization of multiple (currently 36) molecular constituents, throughout a 1-mm3 sample. What this means is that it is now possible to construct the wiring diagram of a neural circuit, consisting of a few 100 million to a billion synapses with precise description of the molecular constituents. We believe that this kind of information will enable researchers to begin to comprehend the proper function of neural circuits and, importantly, to begin to understand how it is that the various neurodegenerative processes present and progress. As alluring as this prospect is, Array Tomography has been used in relatively few studies following the inaugural publication in 2007 (Micheva and Smith, 2007), due to the complexity of the method and the cost of establishing it in the lab of an individual investigator. The commercial opportunity is to offer Array Tomography as a service to the research community. We believe this is the best way to bring the power of the method to bear on problems in neuroscience, cancer research, and medical diagnostic and therapeutic development. To that end, in this proposal we seek to refine the procedures developed in the Smith laboratory so that it will be possible to offer array tomography as a service to the academic and industrial communities. Specifically, we propose to develop a single-purpose imaging instrument, including control software that will allow a many-fold increase in tissue slice imaging. In addition, we propose to develop an image storage and retrieval system to enhance the commercial use of array tomography. PUBLIC HEALTH RELEVANCE: Neurodegenerative diseases, such as Alzheimer's and Parkinson's are becoming more and more prevalent as the population ages. Efforts to develop treatments for these diseases have been hampered by a lack of technologies that provide "big picture" information about how these diseases progress. We propose to develop a technology for high-resolution microscopic analysis of large brain areas to more fully understand the cellular pathologies caused by these diseases so that more effective treatments can be discovered.