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

• 批准号: 10322655
• 负责人: Matthew Reed Steinhart
• 金额: $ 5.18万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 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/10322655
• 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; 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; Proteins; Research; Research Personnel; Schwann Cells; Sensory; Structure; System; Tissues; Training Programs; Tumor Suppressor Genes; Tumor Suppressor Proteins; Vertigo; Vestibular Nerve; Work; antagonist; base; 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

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.

抽象的 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不同部位形成 遍布全身的位置。尽管大多数肿瘤生长缓慢，但某些肿瘤的位置 可能会导致严重的功能障碍。其中一种肿瘤类型生长在脑神经前庭支上 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，这种肿瘤类型被称为前庭神经鞘瘤 (VS)，即前庭神经鞘瘤上的大量施万细胞。 前庭神经。由于颅底颅骨元素靠近，VS 可能会导致听力等功能障碍 丧失、平衡问题或面瘫。目前的治疗选择仅限于侵入性手术 可能会造成并发症的手术。目前对发展机制的了解 由于研究仅限于小鼠和简单的人类细胞，因此 VS 的生长受到限制 文化系统。这项拟议的研究将通过在新系统（内部系统）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使用 3D 培养系统逐步分化 多能干细胞。内耳类器官发育出毛细胞、感觉神经元和感觉神经元的完整感觉回路 体外有髓鞘雪旺细胞。我们将通过在我们的茎中引入基因操作来创建这个模型 模仿 NF2 患者遗传学的细胞。在目标 1 中，我们将分析已知的生化途径 这种新的 NF2 内耳类器官对 NF2 患者产生影响。在目标 2 中，我们将评估可药物靶标 为了评估对抗引入的 NF2 突变的治疗效果。这项研究将提供 深入了解 VS 的致瘤过程。