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: 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
• 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

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）是一种遗传条件 整个身体的位置。尽管这些肿瘤的大多数生长缓慢，但某些肿瘤的位置 会引起明显的功能障碍。这些肿瘤类型之一在颅神经的前庭分支上生长 VIII，前庭神经。产生这种肿瘤类型的细胞是schwann细胞，一个神经胶质细胞 类型。因此，这种肿瘤类型被称为前庭造型瘤（VS），在 前庭神经。由于颅底颅底元素的邻近性，VS会引起功能障碍 损失，平衡问题或面部瘫痪。当前的治疗选择仅限于侵入性手术 可以产生并发症的过程。当前有关管理发展机制的知识 由于研究仅限于小鼠和简单的人类细胞，VS的生长受到限制 培养系统。这项拟议的研究将通过在新系统中建模NF2来提供垂直影响 耳机。内耳的器官诱导涉及使用3D培养系统中的逐步差异 多能干细胞。内耳类器官会形成毛细胞，感觉神经元和 体外髓鞘的雪旺细胞。我们将通过在我们的茎中引入遗传操作来创建此模型 模仿NF2患者的遗传学的细胞。在AIM 1中，我们将分析已知的生化途径 在这种新的NF2内耳手机体中，在NF2患者中受到影响。在AIM 2中，我们将评估可吸毒目标 为了评估治疗有效性以抵消引入的NF2突变。这项研究将提供 深入了解VS的致瘤过程