High-throughput optical investigation into intact large-scale nervous systems for Alzheimers disease

项目摘要 阿尔茨海默病(AD)是一种不可逆转的神经退行性疾病，其根本原因在以下方面不佳- 站着。虽然已经进行了许多研究来了解其病理起源，但使用高级 成像技术，目前的发现主要源于对具有LIM的微观系统的研究。 单元格的数量。虽然越来越多的证据表明，不同物种之间的相互作用 横跨整个神经系统的细胞组掌握着AD中那些悬而未决的问题的关键，大型- 目前的成像技术限制了比例尺的体积调查。第一，所使用的微尺度方法 在传统的组织病理学中，如电子显微镜或光学显微镜，需要广泛的组织切片以 较厚的样本，导致成像时间延长，以及从2D图像进行3D重建的难度 到组织变形。另一方面，ffi的空间分辨率不高，分子种类有限，fi市 像MR/PET/CT这样的大尺度方法已经使它们对病理学研究的吸引力降低。因此， 该项目的目标是开发一种光学成像方法，不仅提供高分辨率和 分子对比剂适用于AD模型小鼠神经系统的病理，但也适用于ff-En-En。 为当今许多AD研究所需的大规模调查提供高通量支持。这 提案计划通过创建相干光学成像设备来满足上述成像需求，以支持 通过开发新的组织处理方法来实现高通量和高分辨率，以实现ffER 通过建立帮助生物学解释的计算工具，在完整的组织中进行分子对比 成像结果。预计拟议研究的结果将是一套新的研究工具， 通过全脑大数据采集和分析，促进对AD小鼠模型的大规模队列研究。这 指导项目的目的是帮助PI(建人博士)实现他获得研究指标的目标。 吊坠。通过拟议的研究，私人助理将从他的导师那里获得补充的专业知识， 领先的科学家团队包括Brett Bouma博士(光学成像)、Bradley Hyman博士(神经学和 AD)，Sangeeta Bhatia博士(纳米医学和组织工程)，Tayyaba Hasan博士(光动力疗法- APY)、Edward Boyden博士(神经科学和光遗传学)和Bruce Fischl博士(计算神经成像- ING和MRI)。这一结合的技术力量将与职业发展技能培训相结合， 促进PI转变为生物医学fi领域的独立研究员。私家侦探将会- 该项目主要在马萨诸塞州总医院的威尔曼光医学中心进行，该中心 周围环绕着几所世界著名的生活和体育科学研究机构- 感觉到了。利用PI导师的支持，他将有机会访问许多研究机构，网址为 哈佛大学和麻省理工学院的更大社区。享受这种高度多学科和协作的研究 在这种环境下，任健博士将承担这项导师式的研究，并过渡到他的研究独立性。

Project Summary Alzheimer’s disease (AD) is an irreversible neurodegenerative disease with its underlying cause poorly under- stood. Although many research have been conducted to understand its pathological origin using advanced imaging technologies, current discoveries have mainly stemmed from studies on microscopic systems with lim- ited number of cells. While increasingly many evidences have indicated that the interaction among various groups of cells across the entire nervous system holds the key to those unanswered questions in AD, large- scale volumetric investigation are limited by current imaging technologies. First, microscale methods used in conventional histopathology, such as electron or light microscopy, require extensive tissue sectioning for thick samples, leading to prolonged imaging time and the difficulty of 3D reconstruction from 2D images due to tissue deformation. On the other end, insufficient spatial resolution and limited molecular specificity of macroscale approaches, such as MR/PET/CT, have made them less attractive for pathological studies. Thus, the goal of this project is to develop an optical imaging method that not only provides high resolution and molecular contrast suitable for the pathology of the nervous systems in AD mouse models, but also offers en- abling high-throughput for those large-scale investigations demanded by many of today’s AD research. This proposal plans to address the above imaging needs by creating coherent optical imaging apparatus to pro- vide the enabling high-throughput and high resolution, by developing new tissue processing methods to offer the molecular contrast in intact tissues, by building computational tools to assist the biological interpretation of imaging results. The outcome of the proposed research is expected to be a set of new research tools that facilitate large-cohort studies on AD mouse models with brain-wide big-data acquisition and analysis. This mentored project is aimed to facilitate the PI (Dr. Jian Ren) to achieve his goal of obtaining research inde- pendence. Through the proposed research, the PI will obtain complementary expertise from his mentors, a team of leading scientists including Dr. Brett Bouma (optical imaging), Dr. Bradley Hyman (neurology and AD), Dr. Sangeeta Bhatia (nanomedicine and tissue engineering), Dr. Tayyaba Hasan (photodynamic ther- apy), Dr. Edward Boyden (neuroscience and optogenetics), and Dr. Bruce Fischl (computational neuroimag- ing and MRI). This combined technical strength will be integrated with training on career development skill, facilitating the transition of the PI to an independent investigator in the biomedical field. The PI will con- duct this project mainly in the Wellman Center for Photomedicine at Massachusetts General Hospital, which is surrounded by several world-renowned universities and research institutions in both life and physical sci- ences. Leveraging the support from the PI’s mentors, he will have access to numerous research facilities at the greater community of Harvard and MIT. Enjoying this highly multidisciplinary and collaborative research environment, Dr. Jian Ren will undertake this mentored research and transition to his research independence.