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

对阿尔茨海默病的完整大规模神经系统进行高通量光学研究

• 批准号: 10390770
• 负责人: Jian Ren
• 金额: $ 13.37万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390770
• 关键词: Alzheimer' s Disease; BDKRB2 gene; Body mass index; Investigation; Nervous system structure; Optics; Proto-Oncogene Proteins c-akt; Qi; i(7q)

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.

项目摘要 阿尔茨海默氏病（AD）是一种不可逆的神经退行性疾病，其潜在的原因很少。尽管已经进行了许多研究，以使用高级成像技术了解其病理起源，但当前的发现主要来自对细胞数量有限的微观系统的研究。尽管越来越多的证据表明，整个神经系统中各组细胞之间的相互作用是AD中那些未解决问题的关键，但LargesCale的体积研究受到当前成像技术的限制。首先，用于传统组织病理学中使用的显微镜​​方法，例如电子或光学显微镜，需要大量的厚样品组织切片，从而导致长时间的成像时间和由于组织变形引起的2D图像的3D重建难度。另一方面，宏观方法方法（例如MR /PET /CT）的空间分辨率不足和有限的分子特异性使它们在病理学研究中的吸引力降低了。因此，该项目的目标是开发一种光学成像方法，该方法不仅提供了适用于AD小鼠模型中神经系统病理的高分辨率和分子对比度，而且还为当今许多AD研究所需的那些大规模研究提供了高通量。该提案计划通过创建连贯的光学成像设备来满足上述成像需求，以通过开发新的组织加工方法来提供高通量和高分辨率，以提供完整组织中的分子对比，并通过构建计算工具来帮助成像结果的生物学解释。拟议研究的结果预计将是一组新的研究工具，可促进对AD小鼠模型进行大脑范围大数据获取和分析的大型研究。这个指导的项目旨在促进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互补的专业知识，他的导师团队，包括Brett Bouma博士（光学成像），Bradley Hyman博士，Bradley Hyman博士（Neurology and AD），Sangeeta Bhatia博士（纳米医学和组织工程），Tayyaba Hasan Hasan（Tayyaba Hasan and Brriouse博士），Neuros Bruliouse博士（Neuros），Neuroct and Brriouse博士（Neuroscent） Fischl（计算神经影像学和MRI）。这种结合的技术实力将与职业发展技能的培训相结合，从而促进了PL向生物医学领域的独立研究者的过渡。 PL将主要在马萨诸塞州综合医院的Wellman摄影医学中心进行该项目，该医院被生活和身体科学的几所世界知名大学和研究机构所包围。利用PL的导师的支持，他将获得哈佛大学和麻省理工学院大社区的众多研究设施。 Jian Ren博士享受这种高度学科和协作的研究环境，将进行这项指导的研究并过渡到他的研究独立性。