Human Ear Cellular Atlas

人耳细胞图谱

• 批准号: 10605053
• 负责人: Alan Gi-Lun Cheng
• 金额: $ 80.33万
• 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/10605053
• 关键词: 3-Dimensional; 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; Data; Data Analyses; Databases; Disease; Dissociation; Doctor of Philosophy; Ear; Education and Outreach; Educational Materials; Educational workshop; Epithelial; Equilibrium; Event; Excision; Faculty; Fetal Tissues; Gene Expression; Gene Proteins; Hearing; Hearing problem; Histologic; Histology; Hour; Human; Image; Imaging Device; Imaging Techniques; Immunohistochemistry; In Situ Hybridization; International; Investigation; Knowledge; Labyrinth; Linear Regressions; Maps; Medical; Medical Records; Messenger RNA; Methods; Molecular; Molecular Profiling; Morphology; Operative Surgical Procedures; Optical Coherence Tomography; Optics; Organ; Organ Donor; Outcome; Oval Window; Participant; Patients; Perilymph; Persons; Pharmacology; 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; base; 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; 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.

抽象的： 听力和平衡疾病在全球范围内几乎十亿人禁用障碍，但实际上没有 这些疾病的药理或生物学疗法。这种令人震惊的医学状态与 更明亮的科学状态，许多治疗方法在动物模型中表现出效率。这 难题反映了一个事实，即动物模型和人类之间存在重要差异，我们 对人类的听觉和前庭器官的分子特征有不完全的了解 内耳，成年人类内耳组织不容易用于测试有希望的疗法。我们 提议通过定义正常的人类内耳的分子构成解决这个难题 组织（AIM 1），描述未经处理的人内部的三维（3D）细胞结构 耳朵（AIM 2），培训新的和既定的研究人员（AIM 3），并提高对人类的认识 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，以从 已故的器官捐献者通常具有正常的听觉和前庭功能。我们已经开始组装 由病历，单细胞转录组和前庭组织的组织学部分组成的注册表 （utrecles）。同时，我们已经用前庭切型瘤患者的乌尔特里斯（Utretiles）增强了注册表 进行手术切除。在这里，我们建议增加器官捐赠者和前庭的招聘 Schwannoma患者并扩展我们的注册表以包括所有内耳感觉器官并产生分子 成年人类内耳的细胞图集（AIM 1）。将收集，分析其他组织和围绕膜 与更广泛的基因和蛋白质验证的更广泛的科学界分享。此外，我们将使用 微型，柔性成像探针我们开发了基于微光学相干断层扫描（µOCT） 快速尸检尸体上的iNomroscopicy生成3D Intact，未加工的人类的光细胞图集 内耳（目标2）。将组装第二个注册表，由分析的数字化μoct-histology图像组成 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 - 科学家，以及通过动手采购和成像人类内耳组织的技术的研究人员 在培训，模拟手术和教学研讨会上（AIM 3）。最后，我们将提高学习的认识 人类内耳组织通过外展活动，发布我们的资源，数据共享和合作 （目标4）。 完成这个五年计划后，我们将组装并共享一个分子和光单元 科学界对人内耳的地图集，增加了对这一资源的认识和利用。