Modeling Neurofibromatosis Type 2 with Inner Ear Organoids

摘要 神经纤维瘤病2(NF2)是一种遗传性疾病，在这种情况下，特定类型的肿瘤在不同的 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。其中一种肿瘤生长在脑神经的前庭支上。 ，前庭耳蜗神经。导致这种肿瘤类型的细胞是雪旺细胞，一种神经胶质细胞 打字。因此，这种肿瘤类型被称为前庭神经鞘瘤(VS)，即位于前庭神经鞘瘤上的一团雪旺细胞。 前庭神经。由于接近颅底颅骨元素，aVS可导致听力障碍。 失落、平衡问题或面部瘫痪。目前的治疗选择仅限于侵入性外科手术。 可能会造成并发症的程序。关于管理发展的机制的最新知识 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 文化体系。这项拟议的研究将通过在一个新的系统内对NF2进行建模来提供垂直影响 耳机。内耳器官诱导涉及3D培养系统中的逐步分化，使用 多能干细胞。内耳有机体发育毛细胞、感觉神经元和 体外培养成髓鞘雪旺细胞。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 在NF2患者中受影响的是这种新的NF2内耳有机化合物。在目标2中，我们将评估可用药目标 以评估对抗引入的NF2突变的治疗效果。这项研究将提供 洞察VS的致瘤过程。

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.