Phenotypic Determinants of Vestibular Schwannomas

前庭神经鞘瘤的表型决定因素

• 批准号: 7596919
• 负责人: D BRADLEY WELLING
• 金额: $ 30.16万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-10 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596919
• 关键词: Acoustic Neuroma; Affect; Age of Onset; Base Pairing; Bilateral; Biological; Biological Assay; Biometry; Blinded; Blood; Blood Cells; Brain Stem; Categories; Cellular Morphology; Classification; Clinical; Cluster Analysis; Code; Consult; Cranial Nerves; DNA; DNA Sequence; DNA-Protein Interaction; Data; Data Analyses; Development; Diagnosis; Electrophoretic Mobility Shift Assay; Elements; Endoglin; Epitopes; Equilibrium; Facial nerve structure; Facial paralysis; Freezing; Future; Gene Chips; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Genetic Polymorphism; Genetic Transcription; Genomics; Genotype; Growth; Hearing; Histologic; Human; Hyperplasia; Immunohistochemistry; Individual; Institutes; Knockout Mice; Laboratories; Letters; Life; Loss of Heterozygosity; Measures; Methods; Methylation; Microarray Analysis; Microinjections; Modification; Molecular Profiling; Morbidity - disease rate; Mosaicism; Mus; Mutation; Mutation Analysis; Myelin Basic Proteins; Natural History; Neurilemmoma; Neurofibromatoses; Neurofibromatosis 2; Neurofibromin 2; Northern Blotting; Nucleic Acid Regulatory Sequences; Ohio; Outcome Study; Paraffin Embedding; Paresthesia; Partner in relationship; Pathway interactions; Patients; Pattern; Pharmacologic Substance; Phenotype; Play; Polymerase Chain Reaction; Promoter Regions; Proteins; RNA; RNA Splicing; Reporter; Research; Research Personnel; Reverse Transcription; Ribonucleases; Role; Sampling; Schwann Cells; Screening procedure; Severities; Signal Pathway; Signal Transduction; Signaling Protein; Site; Solid; Source; Specimen; Staining method; Stains; Statistical Data Interpretation; System; Testing; Therapeutic; Time; Tissue Sample; Tissue-Specific Gene Expression; Tissues; Transcriptional Regulation; Transgenes; Transgenic Mice; Transgenic Organisms; Treatment Protocols; Trigeminal System; Tumor Biology; Tumor Suppressor Genes; Tumor Tissue; Universities; Up-Regulation; Variant; base; cDNA Arrays; design; expression vector; interest; male; medical schools; promoter; protein expression; research study; tumor; tumorigenesis; web site

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.

描述（由申请人提供）：人类前庭神经鞘瘤可导致与听力和平衡丧失，面瘫和感觉异常相关的发病率，偶尔会危及生命的脑干压迫。前庭神经鞘瘤可分为三大类：单侧自发性、2型神经纤维瘤病（NF2）相关和囊型前庭神经鞘瘤。虽然在临床上非常不同，但神经鞘瘤肿瘤类型间表型变异的来源目前尚不清楚，但具有很大的临床意义。此外，由于缺乏对基本肿瘤生物学的了解，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建议的主题。nf2相关的前庭神经鞘瘤的特征是双侧肿瘤表现。NF2历来分为侵袭性和轻度两种。已知前庭神经鞘瘤在神经纤维瘤病2 （NF2）肿瘤抑制基因中存在突变；然而，并不是每个肿瘤都携带nf2编码区突变。已经提出了NF2调控区域突变或甲基化的可能作用。本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。本研究需要验证的主要假设是：1)转录调控在前庭神经鞘瘤的发生中起作用；2)特异性生长信号通路在前庭神经鞘瘤中被解除调控，从而改变表型表达。为了支持这些假设，提出了四组实验。在Specific Aim 1中，他们将研究NF2基因的调控区在神经鞘瘤中的作用，当编码区未发现突变时。特异性Aim 2将在转基因小鼠中检测RhoB是否是雪旺细胞中NF2蛋白的重要下游信号靶点。在第三个特异性目标中，他们将进行类似的转基因分析，在雪旺细胞中过度表达内啡肽。这将通过将RhoB/内啡肽转基因小鼠与条件7vjr2敲除小鼠交配来完成，以确定是否有任何表型增强。在Specific Aim 4中，他们将继续评估可能影响神经鞘瘤肿瘤类型表型表达的差异表达基因。本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。