Human Ear Cellular Atlas

人耳细胞图谱

• 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
• 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

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.

摘要： 听力和平衡障碍使全世界近5亿人残疾，但几乎没有 用于这些疾病的药理学或生物学疗法。这种令人担忧的医学状况与 许多治疗方法在动物模型中显示出疗效。这 这个难题反映了一个事实，即动物模型和人类之间存在着重要的差异， 对人类听觉和前庭器官的分子特征了解不完全 内耳，且成人内耳组织不容易用于测试有希望治疗。我们 我建议通过定义正常的、活的人类内耳的分子组成来解决这个难题 组织（目的1），描述了未加工的人类内部组织的三维（3D）细胞结构 培训新的和已建立的调查人员（目标3），以及提高对人类 内耳研究（目标4）。 为了支持这一方法，我们设计了一种手术方法， 通常具有正常听觉和前庭功能的已故器官捐献者。我们已经开始组装 包括病历、单细胞转录组和前庭组织的组织学切片的注册表 （胞果）。与此同时，我们增加了前庭神经鞘瘤患者椭圆囊的登记 接受手术切除在这里，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，包括所有内耳感觉器官，并产生一个分子 成人内耳的细胞图谱（Aim 1）。将收集、分析和分析其他组织和外淋巴液， 与更广泛的科学界分享，用于基因和蛋白质验证。此外，我们将使用 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 在快速尸检尸体上进行显微内镜检查，以生成3D完整的未处理人类的光学细胞图谱 内耳（目标2）。将组装第二个登记研究，包括分析的数字化µ OCT组织学图像 借助线性回归和人工智能工具。第三，我们将培训临床医生，临床医生- 科学家和研究人员通过手获取和成像人类内耳组织的技术， 培训、模拟手术和教学研讨会（目标3）。最后，我们将提高学习意识 通过外展活动，宣传我们的资源，数据共享和合作， (Aim 4）. 在这个为期5年的计划完成后，我们将组装和共享一个分子和光学细胞 人类内耳地图集，并提高科学界对这一资源的认识和利用。