Function of Merlin, a Drosophila NF2 Gene Homologue

果蝇 NF2 基因同源物 Merlin 的功能

• 批准号: 8610358
• 负责人: Richard G Fehon
• 金额: $ 32.65万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8610358
• 关键词: Adherens Junction; Adult; Apical; Attention; Benign; Biological Models; Cell Proliferation; Cell membrane; Cell physiology; Cell surface; Cells; Cytoplasm; Development; Disease; Drosophila genus; Drosophila merlin; Epithelial Cells; Family; Fertilization; Funding; Genes; Genetic; Goals; Homologous Gene; Human; Individual; Inherited; Laboratories; Lead; Life; Mammalian Cell; Mammals; Mediating; Membrane; Membrane Microdomains; Modeling; Molecular; Molecular Genetics; Monomeric GTP-Binding Proteins; Mus; Mutation; Neurofibromatosis 2; Neurofibromin 2; Neurons; Organism; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Proteins; Recruitment Activity; Research; Role; Signal Transduction; Signal Transduction Pathway; Sterility; Symptoms; Testing; Therapeutic Agents; Tissues; Transcription Coactivator; Tumor Suppression; Tumor Suppressor Proteins; Work; bilateral vestibular Schwannoma; carcinogenesis; cell growth; deafness; design; disease phenotype; ezrin; fly; gene function; insight; member; moesin; mutant; neuronal tumor; positional cloning; protein 4.1; public health relevance; radixin protein; receptor; research study; rho; trafficking; transcription factor; tumor

DESCRIPTION (provided by applicant): Neurofibromatosis type 2 (NF2), a dominantly inherited disease, is caused by mutations in Merlin (Schwannomin), a member of the Protein 4.1 superfamily. Symptoms of NF2, which usually appear by early adult life, are caused by the formation of bilateral vestibular Schwannomas (resulting in deafness) and other benign tumors. The cellular functions of Merlin and its role in tumor suppression are still largely unknown, though recent studies in our laboratory and others have made significant progress. Identifying specific proteins and signal transduction pathways with which Merlin interacts is especially important because these partners may act as genetic modifiers of NF2 disease phenotypes and provide potential targets for therapeutic agents. The common fruit fly, Drosophila, has proven to be a useful model system for understanding gene function in the context of a developing organism. The overall goal of this proposal is therefore to examine the cellular functions of Merlin and its functional partner Expanded in Drosophila, particularly in relation to the control of cell proliferation by the Hippo pathway. In the next funding period, we plan to continue our studies of Merlin and Expanded function in developing organisms and in individual cells. Specifically, the proposed experiments will: 1) Elucidate functional interactions between Merlin/Expanded and the HSW pathway. Specifically we will test the hypothesis that Expanded functions downstream of Hippo to regulate the transcriptional coactivator Yorkie. 2) Understand the role of Merlin and Expanded in regulating receptor localization and availability at the plasma membrane. 3) Examine the role of signaling by the Hippo, Salvador, Warts pathway on regulating receptor abundance at the cell surface. These experiments are expected to provide insights into the functions of Merlin, Expanded and the Hippo pathway in regulating proliferation. Thus they will contribute to our understanding of human NF2, tumor suppression in general, and carcinogenesis. In addition, the proposed experiments should lead to a better understanding of the cellular processes that establish specialized membrane domains in epithelial cells and neurons. Finally, these studies should contribute to work on the mechanisms by which cellular interactions function to control cell growth and determine cell fate during development.

描述（由申请人提供）：神经纤维瘤病2型（NF2）是一种主要遗传性疾病，是由蛋白4.1超家族的梅林（Schwannomin）突变引起的。 NF2的症状通常是由成年早期出现的，是由双侧前庭schwannomas（导致耳聋）和其他良性肿瘤的形成引起的。 Merlin的细胞功能及其在肿瘤抑制中的作用仍然是未知的，尽管我们的实验室和其他研究取得了重大进展。识别梅林相互作用的特定蛋白质和信号转导途径尤其重要，因为这些伴侣可以充当NF2疾病表型的遗传修饰剂，并为治疗剂提供潜在的靶标。事实证明，普通的果蝇果蝇是一种有用的模型系统，可在发育中的生物体中理解基因功能。因此，该提案的总体目标是检查果蝇中扩展的梅林及其功能伙伴的细胞功能，尤其是与河马途径控制细胞增殖的关系。 在下一个资金期间，我们计划继续对Merlin的研究，并扩大在开发生物和单个细胞中的功能。具体而言，提出的实验将：1）阐明Merlin/Expanded和HSW途径之间的功能相互作用。 具体而言，我们将检验以下假设，即扩大了河马下游功能以调节转录共激活因子约克。 2）了解梅林的作用，并扩展在调节质膜的受体定位和可用性中。 3）检查河马，萨尔瓦多，疣途径在调节细胞表面受体丰度的作用。 这些实验有望提供有关Merlin，扩展和河马途径调节增殖功能的见解。因此，它们将有助于我们对人NF2，肿瘤抑制和致癌作用的理解。此外，提出的实验应更好地了解在上皮细胞和神经元中建立专门的膜结构域的细胞过程。最后，这些研究应有助于研究细胞相互作用来控制细胞生长并确定发育过程中细胞命运的机制。