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: 10782614
• 负责人: Jian Ren
• 金额: $ 24.9万
• 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 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10782614
• 关键词: 3-Dimensional; Address; Affect; Algorithms; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Animals; Area; Axon; Big Data; Biochemistry; Biological; Biological Sciences; Brain; Brain imaging; Brain region; Cells; Chemistry; Cohort Studies; Communities; Complex; Contrast Media; Data; Data Analyses; Detection; Disease; Electron Microscopy; Engineering; Environment; Etiology; General Hospitals; Goals; Graph; Histologic; Histopathology; Image; Image Analysis; Imaging Device; Imaging technology; Impaired cognition; Individual; Institution; Intervention; Investigation; Label; Light; Magnetic Resonance Imaging; Maps; Massachusetts; Measurement; Mentors; Methods; Microscope; Microscopic; Molecular; Mus; Neighborhoods; Nervous System; Neurodegenerative Disorders; Neurology; Neurosciences; Optics; Outcome; PET/CT scan; PUVA Photochemotherapy; Pathologic; Pathology; Patients; Process; Progressive Disease; Property; Proteins; Research; Research Personnel; Resolution; Sampling; Scientist; Social Impacts; Software Engineering; Specificity; Structure; System; Techniques; Testing; Thick; Time; Tissue Engineering; Tissues; Training; Universities; Visualization; Work; career development; cognitive function; computerized tools; contrast imaging; data acquisition; economic impact; image processing; imaging approach; imaging capabilities; imaging modality; imaging system; improved; innovation; light microscopy; microscopic imaging; mouse model; multidisciplinary; nanomedicine; nanoscale; optical imaging; optogenetics; physical science; reconstruction; research facility; response; signal processing; skill acquisition; stem; three-dimensional visualization; tissue processing; tomography; tool; tractography

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.

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种不可逆的神经退行性疾病，其根本原因尚不清楚， 站着。尽管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，目前的发现主要来自于对具有limm的微观系统的研究， 有限数量的细胞。虽然越来越多的证据表明， 整个神经系统的细胞群掌握着AD中那些未解之谜的关键， 大规模的体积研究受到当前成像技术的限制。第一，使用的微尺度方法 在常规组织病理学中，例如电子或光学显微镜，需要广泛的组织切片， 厚的样本，导致成像时间延长，并且由于 组织变形另一方面，空间分辨率不足和分子特异性有限， 宏观尺度的方法，如MR/PET/CT，已经使它们对于病理学研究不那么有吸引力。因此，在本发明中， 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， 分子对比适用于AD小鼠模型中神经系统的病理学，但也适用于神经系统的病理学， 为当今许多AD研究所需的大规模研究提供高通量。这 该提案计划通过创建相干光学成像设备来解决上述成像需求， 通过开发新的组织处理方法， 完整组织中的分子对比，通过建立计算工具来辅助生物学解释 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 指导项目旨在帮助PI（Jian Ren博士）实现其获得研究指标的目标， 悬垂。通过拟议的研究，首席研究员将从他的导师那里获得互补的专业知识， 由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Fischl博士（计算神经成像， 和MRI）。这种综合技术力量将与职业发展技能培训相结合， 促进PI转变为生物医学领域的独立研究者。私家侦探会- 该项目主要在马萨诸塞州总医院的韦尔曼光医学中心进行， 被几所世界知名的生命科学和物理科学大学和研究机构所包围， 有问题。利用PI导师的支持，他将有机会使用位于 哈佛和麻省理工的大社区。享受这种高度多学科和协作研究 在这种环境下，Jian Ren博士将进行这项指导性研究，并过渡到他的研究独立性。