Human Ear Cellular Atlas

摘要： 听力和平衡障碍使全球近5亿人致残，但实际上没有 治疗这些疾病的药物或生物疗法。这种令人震惊的医学状况与 更光明的科学状态，许多治疗方法在动物模型中显示出有效性。这 疑难解答反映了这样一个事实，即动物模型和人类之间有重要的区别，我们 对人类听觉和前庭器官的分子特征了解不完全 内耳，而成人内耳组织并不容易用于测试有希望的疗法。我们 建议通过定义正常的活体人类内耳的分子组成来解决这个难题 组织(目标1)，描述未经处理的人体内部的三维(3D)细胞结构 EAR(目标2)，培训新的和现有的调查员(目标3)，并提高对人类的认识 内耳研究(目标4)。 为了支持这一方法，我们设计了一种外科方法，从 通常听力和前庭功能正常的已故器官捐赠者。我们已经开始组装了 由前庭组织的医疗记录、单细胞转录本和组织切片组成的登记表 (胞果)。同时，我们用前庭神经鞘瘤患者的椭圆形扩大了登记范围。 正在进行手术切除的。在这里，我们建议增加器官捐赠者和前庭的招募 神经鞘瘤患者，并扩大我们的注册范围，包括所有内耳感觉器官并产生一个分子 成人内耳细胞图谱(目标1)。将收集、分析和分析更多的组织和外淋巴 与更广泛的科学界共享以进行基因和蛋白质验证。此外，我们将使用 我们开发的微型、灵活的成像探头用于基于微光学相干层析成像(µOCT) 在快速尸检身体上进行内窥镜检查，以生成3D完整、未经处理的人类的光学细胞图谱 内耳(目标2)。将汇编第二个注册表，其中包括分析的数字化组织学图像 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- 关于培训、模拟手术和授课讲习班(目标3)。最后，我们将提高学习的意识 人类内耳组织通过外展活动、宣传我们的资源、数据共享和协作 (目标4)。 在这项为期5年的计划完成后，我们将组装并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。

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.