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Modeling Neurofibromatosis Type 2 with Inner Ear Organoids

使用内耳类器官模拟 2 型神经纤维瘤病

基本信息

批准号：
10544337
负责人：
Matthew Reed Steinhart
金额：
$ 5.52万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-31 至 2025-01-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10544337
关键词：
Acoustic Nerve Acoustic Neuroma Actins Address Adherent Culture Affect Afferent Neurons Axon Biochemical Pathway Biology CRISPR/Cas technology Cell Culture System Cell Proliferation Cells Cephalic Code Communities Complex Cytoskeleton Development Disease Drug Targeting Effectiveness Elements Embryo Equilibrium Facial paralysis Foundations Functional disorder Genes Genetic Genetic Diseases Goals Growth and Development function Hair Cells Human In Vitro Investigation Knock-out Knowledge Laboratories Labyrinth Location Modeling Mus Mutation Neurilemmoma Neurofibromatosis 2 Neurofibromin 2 Neuroglia Neurons Operative Surgical Procedures Organogenesis Organoids Pathogenesis Pathway interactions Patients Peripheral Pharmacotherapy Phenocopy Pluripotent Stem Cells Population Process Proliferating Proteins Research Research Personnel Schwann Cells Sensory Structure System Tissues Training Programs Tumor Suppressor Genes Tumor Suppressor Proteins Vertigo Vestibular Nerve Work antagonist cell type drug development druggable target experience experimental study ezrin genetic manipulation hearing impairment human model human pluripotent stem cell insight moesin mouse model novel radixin protein receptor single-cell RNA sequencing skull base stem cells targeted treatment therapeutic effectiveness therapeutic target three dimensional cell culture tumor tumorigenic

项目摘要

ABSTRACT Neurofibromatosis Type 2 (NF2) is a genetic condition in which specific types of tumors form in various locations throughout the body. Though the majority of these tumors grow slowly, the location of certain tumors can cause significant dysfunction. One of these tumor types grows on the vestibular branch of cranial nerve VIII, the vestibulocochlear nerve. The cells which gives rise to this tumor type is the Schwann cell, a glial cell type. Thus, this tumor type is termed a vestibular Schwannoma (VS), a mass of Schwann cells on the vestibular nerve. Due to the proximity of skull base cranial elements, a VS can cause dysfunction like hearing loss, balance issues, or facial paralysis. The current treatment options are limited to invasive surgical procedures which can create complications. Current knowledge of the mechanisms governing the development and growth of VS is limited due to the fact that research has been restricted to mouse and simple human cell culture systems. This proposed study will provide vertical impact by modeling NF2 in a new system, the inner ear organoid. Inner ear organoid induction involves step-wise differentiation in a 3D culture system using pluripotent stem cells. Inner ear organoids develop full sensory circuits of hair cells, sensory neurons, and myelinating Schwann cells in vitro. We will create this model by introducing a genetic manipulation in our stem cells which mimics the genetics of NF2 patients. In Aim 1, we will analyze biochemical pathways known to be affected in NF2 patients in this new NF2 inner ear organoid. In Aim 2, we will evaluate druggable targets in order to assess therapeutic effectiveness to counteract the introduced NF2 mutation. This study will provide insight into the tumorigenic processes of VS.

摘要 2型神经纤维瘤病（NF2）是一种遗传性疾病，其中特定类型的肿瘤在各种疾病中形成。在整个身体的位置。虽然大多数肿瘤生长缓慢，但某些肿瘤的位置会导致严重的功能障碍其中一种肿瘤生长于颅神经前庭分支第八，前庭蜗神经。产生这种肿瘤类型的细胞是雪旺细胞，一种神经胶质细胞类型.因此，这种类型的肿瘤被称为前庭神经鞘瘤（VS），一个雪旺细胞的质量上，前庭神经由于颅底颅骨元件的接近，VS可导致听力等功能障碍失去平衡或面瘫目前的治疗选择仅限于侵入性手术可能造成并发症的手术目前对发展机制的认识由于研究仅限于小鼠和简单的人类细胞，文化体系。这项拟议的研究将通过在一个新的系统中对NF2进行建模来提供垂直影响，耳类器官内耳类器官诱导涉及在3D培养系统中使用多能干细胞。内耳类器官发育毛细胞、感觉神经元和体外髓鞘化雪旺细胞。我们将通过在我们的茎中引入基因操作来创建这个模型模拟NF2患者基因的细胞。在目标1中，我们将分析已知的生物化学途径， NF2患者在这种新的NF2内耳类器官中受到影响。在目标2中，我们将评估药物靶点，以评估对抗引入的NF 2突变的治疗效果。本研究将提供深入了解VS的致瘤过程。