Phenotypic Determinants of Vestibular Schwannomas

描述(申请人提供)：人类前庭神经鞘瘤可导致与听力和平衡丧失、面部瘫痪和感觉异常相关的发病率，有时还会危及生命。前庭神经鞘瘤可分为三大类--单侧自发性、神经纤维瘤病2型(NF2)相关和囊性前庭神经鞘瘤。虽然在临床上很不同，但神经鞘瘤肿瘤类型之间表型差异的来源目前尚不清楚，但临床上有很大的兴趣。此外，由于缺乏对基础肿瘤生物学的了解，最佳治疗方案尚不清楚。在这三种类型的肿瘤中，NF2相关的前庭神经鞘瘤是当前提案的主题。NF2相关前庭神经鞘瘤的特点是双侧肿瘤表现。NF2在历史上被细分为进攻型和轻型型。众所周知，前庭神经鞘瘤含有神经纤维瘤病2(NF2)肿瘤抑制基因突变；然而，并不是每个肿瘤都携带NF2编码区的突变。已经提出了NF2调节区中突变或甲基化的可能作用。这项研究的长期目标是进一步识别和了解影响前庭神经鞘瘤表型表达的因素。这项研究的主要假设是：1)转录调控在前庭神经鞘瘤的发生中起作用，2)在前庭神经鞘瘤中，特定的生长信号通路被解除调控，从而改变了表型表达。为了支持这些假设，我们提出了四组实验。在特定的目标1中，他们将在编码区没有发现突变的情况下，研究NF2基因的调节区在神经鞘瘤中的作用。特异性目标2将在转基因小鼠中检查RhoB是否是雪旺细胞中NF2蛋白的重要下游信号目标。在第三个特定目标中，他们将进行类似的转基因分析，以在雪旺细胞中过度表达endoglin。这将通过将RhoB/endoglin转基因小鼠与条件7Vjr2基因敲除小鼠交配来完成，以确定是否有任何表型的增强。在特定的目标4中，他们将继续评估差异表达的基因，这些基因可能影响神经鞘瘤肿瘤类型之间的表型表达。这项研究的成功完成将进一步阐明前庭神经鞘瘤形成的重要途径，为未来药物治疗的发展提供良好的潜力。

DESCRIPTION (provided by applicant): Vestibular schwannomas in humans can cause morbidity associated with hearing and balance loss, facial paralysis and paresthesias, and occasionally life-threatening brainstem compression. Vestibular schwannomas can be divided into three general categories - unilateral spontaneous, neurofibromatosis type 2 (NF2) associated, and cystic-type vestibular schwannomas. Although quite distinct clinically, the source of phenotypic variation among schwannoma tumor types is currently unknown, but of great clinical interest. Furthermore, the optimal treatment regimens are not known because of a lack of understanding of fundamental tumor biology. Of the three types of tumors, NF2-associated vestibular schwannomas are the subject of the current proposal. The hallmark of NF2-associated vestibular schwannomas is bilateral tumor presentation. NF2 is historically subclassified into an aggressive and a mild form. Vestibular schwannomas are known to harbor mutations in the neurofibromatosis 2 (NF2) tumor suppressor gene; however, not every tumor carries a mutation in the NF2-coding region. A possible role for mutation or methylation in the NF2 regulatory regions has been suggested. The long-term objective of this study is to further identify and understand factors which affect the phenotypic expression of vestibular schwannomas. The principal hypotheses of this study to be tested are that 1) transcriptional regulation plays a role in vestibular schwannoma tumorigenesis and 2) phenotypic expression is altered by specific growth signaling pathways that are deregulated in vestibular schwannomas. In support of these hypotheses, four sets of experiments are proposed. In Specific Aim 1, they will examine the role of the regulatory region of the NF2 gene in schwannomas when mutations have not been identified in the coding region. Specific Aim 2 will examine in transgenic mice whether RhoB is an important downstream signaling target of the NF2 protein in Schwann cells. In the third Specific Aim, they will conduct a similar transgenic analysis to over-express endoglin in Schwann cells. This will be accomplished by mating the RhoB/endoglin transgenic mice with the conditional 7Vjr2-knockout mice to determine if there is any enhancement of the phenotype. In Specific Aim 4, they will continue to evaluate differentially expressed genes, which may influence the phenotypic expression among schwannoma tumor types. Successful completion of this study should further elucidate important pathways of vestibular schwannoma formation with good potential for future development of pharmaco-therapeutics.