High-throughput optical investigation into intact large-scale nervous systems for Alzheimer's disease - Project Summary Alzheimer's disease (AD) is an irreversible neurodegenerative disease with its underlying cause poorly understood. Current discoveries on its pathological origin 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, 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 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 imaging apparatus, such as interferometry and holography, to provide the enabling high-throughput and high resolution, by developing new tissue processing methods to offer the molecular contrast, by building computational tools to assist the biological interpretation of imaging results. The proposed research is expected to generate a set of new research tools that enable large-cohort studies with brain-wide big-data acquisition and analysis. The Pl (Dr. Jian Ren) 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). 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.
