Phenotypic Determinants of Vestibular Schwannomas

前庭神经鞘瘤的表型决定因素

基本信息

批准号：
7220614
负责人：
D BRADLEY WELLING
金额：
$ 30.56万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-10 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7220614
关键词：
Accounting Acoustic Neuroma Adolescence Affect Age of Onset Alleles Analysis of Variance Appearance Astrocytoma Base Pairing Bilateral Biological Biological Assay Biometry Blinded Blood Blood Cells Brain Stem Categories Cellular Morphology Cerebellopontine Angle Neoplasm Classification Clinical Cluster Analysis Code Consult Cranial Nerves Cystic Neoplasm DNA DNA Sequence DNA-Protein Interaction Data Data Analyses Deposition Development Diagnosis Disease Doctor of Medicine Doctor of Philosophy Electrophoretic Mobility Shift Assay Elements Endoglin Endoribonucleases Ependymoma Epigenetic Process Epitopes Equilibrium Excision Exhibits Exons Facial nerve structure Facial paralysis Frameshift Mutation Freezing Future Gene Chips Gene Expression Gene Expression Profile Gene Mutation Genes Genetic Polymorphism Genetic Transcription Genomics Genotype Glioma Growth Hearing Hemosiderin Histologic Human Hyperplasia Immunohistochemistry Individual Institutes Internet Knockout Mice Laboratories Letters Life Localized Location Loss of Heterozygosity Magnetic Resonance Imaging Measures Methods Methylation Microarray Analysis Microinjections Missense Mutation Modification Molecular Profiling Morbidity - disease rate Mosaicism Mus Mutation Mutation Analysis Myelin Basic Proteins Natural History Neurilemmoma Neuro-Oncological Ventral Antigen 2 Neurofibromatoses Neurofibromatosis 2 Neurofibromin 2 Northern Blotting Nucleic Acid Regulatory Sequences Numbers Ohio Onset of illness Other Finding Outcome Study Pancreatic ribonuclease Paraffin Embedding Paresthesia Partner in relationship Pathway interactions Patients Pattern Pharmacologic Substance Phenotype Play Polymerase Chain Reaction Principal Investigator Promoter Regions Protein Isoforms Proteins RNA RNA Splicing Radiation Rate Regulation Reporter Reporting Research Research Personnel Reverse Transcription Ribonucleases Role Sampling Schwann Cells Screening procedure Severities Severity of illness Signal Pathway Signal Transduction Signaling Protein Site Solid Source Specimen Spinal Neoplasms Splice-Site Mutation Staining method Stains Standards of Weights and Measures Statistical Data Interpretation System Testing Therapeutic Thinking Time Tissue Sample Tissue-Specific Gene Expression Tissues Transcriptional Activation Transcriptional Regulation Transgenes Transgenic Mice Transgenic Organisms Treatment Protocols Treatment outcome Trigeminal System Tumor Biology Tumor Suppressor Genes Tumor Tissue Universities Up-Regulation Variant base cDNA Arrays design expression vector hearing impairment interest male medical schools meningioma programs promoter protein expression rapid growth research study tumor tumorigenesis uptake vestibular pathway

项目摘要

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，有时还会导致危及生命的脑干受压。前庭神经鞘瘤可分为三大类：单侧自发性前庭神经鞘瘤、2 型神经纤维瘤病 (NF2) 相关性和囊性前庭神经鞘瘤。虽然临床上相当不同，但神经鞘瘤肿瘤类型之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提案的主题。 NF2 相关前庭神经鞘瘤的特点是双侧肿瘤出现。 NF2 历来分为侵袭性和轻度两种。已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，并非所有肿瘤的 NF2 编码区都携带突变。有人提出了 NF2 调节区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。本研究待测试的主要假设是：1) 转录调控在前庭神经鞘瘤肿瘤发生中发挥作用，2) 表型表达因前庭神经鞘瘤中失调的特定生长信号通路而改变。为了支持这些假设，提出了四组实验。在具体目标 1 中，当编码区尚未发现突变时，他们将检查 NF2 基因调控区在神经鞘瘤中的作用。具体目标 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传导靶标。在第三个具体目标中，他们将进行类似的转基因分析，以在雪旺细胞中过度表达内皮糖蛋白。这将通过将 RhoB/内皮糖蛋白转基因小鼠与条件性 7Vjr2 敲除小鼠交配来确定是否有任何表型增强来完成。在具体目标 4 中，他们将继续评估差异表达的基因，这可能会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应进一步阐明前庭神经鞘瘤形成的重要途径，对于未来药物治疗的发展具有良好的潜力。