Human Ear Cellular Atlas

人耳细胞图谱

基本信息

批准号：
10705836
负责人：
Alan Gi-Lun Cheng
金额：
$ 59.98万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-16 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10705836
关键词：
3-Dimensional Acceleration Acoustic Neuroma Address Adult Animal Model Animals Architecture Archives Artificial Intelligence Atlases Auditory Autopsy Awareness Biological Response Modifier Therapy Cadaver Cataloging Cells Cellular Morphology Cochlea Collaborations Communities Crista ampullaris Cryoultramicrotomy Data Data Analyses Databases Disease Dissociation Doctor of Philosophy Ear Educational Materials Educational workshop Epithelium Equilibrium Event Excision Faculty Fetal Tissues Gene Expression Genes Hearing Hearing problem Histologic Histology Hour Human Image Imaging Device Imaging Techniques Immunohistochemistry In Situ Hybridization Instruction International Investigation Knowledge Labyrinth Linear Regressions Maps Medical Medical Records Medical Students Messenger RNA Methods Molecular Molecular Profiling Morphology Operative Surgical Procedures Optical Coherence Tomography Optics Organ Organ Donor Organ Procurements Outcome Oval Window Participant Patients Perilymph Persons Physiological Postdoctoral Fellow Process Proteins Protocols documentation Publications Publishing Recording of previous events Registries Research Research Personnel Resolution Resources Saccule structure Scanning Electron Microscopy Science Scientist Sensory Specimen State Medicine System Techniques Temporal bone structure Testing Therapeutic Tissue Banks Tissue Donors Tissues Training Training Technics Transcript Translations Utricle structure Validation Vestibule cellular imaging data sharing deafness design doctoral student effective therapy equilibration disorder flexibility hearing impairment high resolution imaging human imaging imaging probe imaging system inner ear diseases insight meetings microendoscopy molecular imaging novel optical imaging outreach pharmacologic programs recruit round window single-cell RNA sequencing social media success tissue archive tool transcriptome validation studies virtual virtual experiments virtual surgery

项目摘要

Abstract: Hearing and balance disorders disable nearly half a billion people worldwide, yet there are virtually no pharmacological or biological therapies for these disorders. This alarming state of medicine coexist with the brighter state of science where numerous therapeutic approaches have shown efficacy in animal models. This conundrum reflects the fact that there are important differences between animal models and humans, that we have an incomplete understanding of the molecular signatures of the auditory and vestibular organs in the human inner ear, and that adult human inner ear tissues are not readily available to test promising therapeutics. We propose to solve this conundrum by defining the molecular makeup of normal, live human inner ear tissues (Aim 1), describing the three-dimensional (3D) cellular architecture of unprocessed human inner ears (Aim 2), training new and established investigators (Aim 3), and enhancing awareness of human inner ear research (Aim 4). In support of this approach, we have designed a surgical method to procure live inner ear tissues from deceased organ donors who typically have normal auditory and vestibular function. We have begun assembling a registry consisting of medical records, single-cell transcriptomes, and histologic sections of vestibular tissues (utricles). In parallel, we have augmented the registry with utricles from vestibular schwannoma patients undergoing surgical resection. Here, we propose to increase the recruitment of organ donors and vestibular schwannoma patients and expand our registry to include all inner ear sensory organs and generate a molecular cell atlas of the adult human inner ear (Aim 1). Additional tissues and perilymph will be collected, analyzed and shared with the broader scientific community for gene and protein validation. Furthermore, we will use a miniature, flexible imaging probe we developed to perform micro-optical coherence tomography (µOCT)-based endomicroscopy on rapid autopsy cadavers to generate an optical cell atlas of the 3D-intact, unprocessed human inner ear (Aim 2). A second registry will be assembled, consisting of digitized µOCT-histology images analyzed with the aid of both linear regression and artificial intelligence tools. Thirdly, we will train clinicians, clinician- scientists, and researchers on the techniques of procuring and imaging human inner ear tissues through hands- on training, simulated surgery, and didactic workshops (Aim 3). Lastly, we will raise awareness of studying human inner ear tissues through outreach activities, publicizing our resources, data sharing, and collaborations (Aim 4). Upon completion of this 5-year program, we will have assembled and shared a molecular and optical cell atlas of the human inner ear and increased awareness and utilization of this resource by the scientific community.

抽象的：听力和平衡障碍导致全球近 5 亿人残疾，但实际上没有这些疾病的药物或生物疗法与药物治疗并存。更光明的科学状态，许多治疗方法已在动物模型中显示出疗效。难题反映了动物模型和人类之间存在重要差异的事实，我们对人类听觉和前庭器官的分子特征不完全了解内耳，并且成人内耳组织不易用于测试有前途的治疗方法。建议通过定义正常活人内耳的分子组成来解决这个难题组织（目标 1），描述未加工的人体内部的三维 (3D) 细胞结构耳朵（目标 2），培训新的和已建立的调查员（目标 3），以及提高人类的意识内耳研究（目标 4）。为了支持这种方法，我们设计了一种手术方法来获取活的内耳组织通常听觉和前庭功能正常的已故器官捐献者我们已经开始集合。由医疗记录、单细胞转录组和前庭组织的组织学切片组成的注册表与此同时，我们还增加了来自前庭神经鞘瘤患者的椭圆囊的登记。在这里，我们建议增加器官捐献者和前庭的招募。神经鞘瘤患者并扩大我们的登记范围以包括所有内耳感觉器官并生成分子将收集、分析和分析成人内耳的细胞图谱（目标 1）。此外，我们将与更广泛的科学界共享基因和蛋白质验证。我们开发的微型灵活成像探头用于执行基于微光学相干断层扫描 (µOCT) 的操作对快速尸检尸体进行内窥镜检查，生成 3D 完整、未处理的人体光学细胞图谱内耳（目标 2）将被组装，由分析的数字化 µOCT 组织学图像组成。第三，我们将在线性回归和人工智能工具的帮助下培训新兵、临床医生。科学家和研究人员致力于通过手工获取人类内耳组织并对其进行成像的技术培训、模拟手术和教学研讨会（目标 3）。通过外展活动、宣传我们的资源、数据共享和合作来了解人类内耳组织（目标 4）。完成这个为期 5 年的计划后，我们将组装并共享分子和光学单元人类内耳图谱以及科学界对该资源的认识和利用的提高。