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

项目摘要 阿尔茨海默病（AD）是一种不可逆的神经退行性疾病，其根本原因知之甚少。虽然已经进行了许多研究，以了解其病理起源使用先进的成像技术，目前的发现主要源于对有限数量的细胞的微观系统的研究。虽然越来越多的证据表明，在整个神经系统中的各种细胞群之间的相互作用是AD中那些未回答的问题的关键，但大规模的体积研究受到当前成像技术的限制。首先，用于常规组织病理学的微尺度方法，例如电子或光学显微镜，需要对厚样品进行大量组织切片，导致成像时间延长，并且由于组织变形而难以从2D图像进行3D重建。另一方面，宏观尺度方法（如MR/PET /CT）的空间分辨率不足和有限的分子特异性使其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，不仅提供适合AD小鼠模型神经系统病理学的高分辨率和分子对比度，而且还为当今许多AD研究所需的大规模研究提供高通量。该提案计划通过创建相干光学成像装置以提供使能的高通量和高分辨率，通过开发新的组织处理方法以提供完整组织中的分子对比度，通过构建计算工具以辅助成像结果的生物学解释来解决上述成像需求。这项研究的成果预计将成为一套新的研究工具，通过全脑大数据采集和分析，促进对AD小鼠模型的大队列研究。这个指导项目旨在帮助Pl（Jian Ren博士）实现其获得研究独立性的目标。通过拟议的研究，Pl将从他的导师那里获得补充专业知识，包括Brett Bouma博士（光学成像），布拉德利海曼博士（神经病学和AD），Sangeeta Bhatia博士（纳米医学和组织工程），Tayyaba Hasan博士（光动力疗法），Edward Boyden博士（神经科学和光遗传学）和布鲁斯费舍尔博士（计算神经成像和MRI）。这一综合技术力量将与职业发展技能培训相结合，促进Pl向生物医学领域独立调查员的过渡。该项目将主要在马萨诸塞州总医院的韦尔曼光医学中心进行，该中心周围有几所世界知名的生命科学和物理科学大学和研究机构。利用从PL的导师的支持，他将有机会获得众多的研究设施，在更大的社区哈佛和麻省理工学院。享受这种高度多学科和协作的研究环境，Jian Ren博士将进行这项指导研究，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 understood. 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 limited 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, largescale 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 enabling 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 provide 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 Pl (Dr. Jian Ren) to achieve his goal of obtaining research independence. Through the proposed research, the Pl 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 therapy), Dr. Edward Boyden (neuroscience and optogenetics), and Dr. Bruce Fischl (computational neuroimaging and MRI). This combined technical strength will be integrated with training on career development skill, facilitating the transition of the Pl to an independent investigator in the biomedical field. The Pl will conduct 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 sciences. Leveraging the support from the Pl'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.