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，其潜在原因尚不清楚。虽然利用先进的成像技术已经进行了许多研究来了解其病理起源，但目前的发现主要来自于对细胞数量有限的微观系统的研究。虽然越来越多的证据表明，整个神经系统不同细胞群之间的相互作用是解决AD这些悬而未决的问题的关键，但目前的成像技术限制了大规模的体积研究。首先，常规组织病理学中使用的微尺度方法，如电子显微镜或光学显微镜，需要对较厚的样本进行广泛的组织切片，导致成像时间延长，并且由于组织变形而难以从2D图像进行三维重建。另一方面，空间分辨率不足和分子特异性有限的大尺度方法，如MR/PET/CT，使它们对病理学研究的吸引力降低。因此，本项目的目标是开发一种光学成像方法，不仅能提供高分辨率和分子对比度，适用于AD小鼠模型的神经系统病理，而且还能为当今许多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设备来满足上述成像需求，以实现高通量和高分辨率，通过开发新的组织处理方法来在完整组织中提供分子对比度，通过建立计算机工具来辅助对成像结果的生物学解释。预计拟议研究的结果将是一套新的研究工具，通过全脑范围的大数据获取和分析来促进对AD小鼠模型的大规模队列研究。这个指导项目的目的是帮助Pl(建人博士)实现他获得研究独立的目标。通过拟议的研究，Pl将从他的导师那里获得互补的专业知识，该团队由领先的科学家组成，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(光动力学疗法)、Edward Boyden博士(神经科学和光遗传学)和Bruce Fischl博士(计算神经成像和MRI)。这一结合的技术力量将与职业发展技能培训相结合，促进将PL转变为生物医学领域的独立调查员。PL将主要在马萨诸塞州总医院的威尔曼光医学中心进行这一项目，该中心周围有几所世界著名的生命科学和物理科学研究机构。利用公共图书馆导师的支持，他将有机会接触到哈佛和麻省理工学院更大社区的许多研究机构。享受这种高度多学科和协作的研究环境，任建人博士将承担这项指导性研究，并过渡到他的研究独立。

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.