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.

项目概要 阿尔茨海默病（AD）是一种不可逆的神经退行性疾病，其根本原因尚不清楚。尽管已经进行了许多研究来利用先进的成像技术来了解其病理起源，但目前的发现主要源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中不同细胞群之间的相互作用是解决 AD 中那些未解答问题的关键，但大规模体积研究受到当前成像技术的限制。首先，传统组织病理学中使用的微尺度方法，例如电子或光学显微镜，需要对厚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 3D 重建。另一方面，MR/PET/CT 等宏观方法的空间分辨率不足和分子特异性有限，使其对病理研究的吸引力降低。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，而且还为所需的大规模研究提供高通量。当今许多 AD 研究表明。该提案计划通过创建相干光学成像设备来提供高通量和高分辨率，通过开发新的组织处理方法来提供完整组织中的分子对比度，通过构建计算工具来协助生物学解释来解决上述成像需求的成像结果。拟议研究的成果预计将是一套新的研究工具，通过全脑大数据采集和分析，促进 AD 小鼠模型的大队列研究。这个指导项目旨在帮助Pl（任健博士）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，导师是一个由顶尖科学家组成的团队，包括Brett Bouma博士（光学成像）、Bradley Hyman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 Bruce Fischl 博士（计算神经影像和核磁共振成像）。这种综合技术实力将与职业发展技能培训相结合，促进 PL 向生物医学领域的独立研究者的过渡。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，该中心周围有多所世界著名的生命科学和物理科学大学和研究机构。在 Pl 导师的支持下，他将能够使用哈佛大学和麻省理工学院的众多研究设施。享受这种高度多学科和协作的研究环境，任健博士将承担这项指导性研究并过渡到他的研究独立性。