Function of Merlin, a Drosophila NF2 Gene Homologue

果蝇 NF2 基因同源物 Merlin 的功能

基本信息

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
项目类别：
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

项目摘要

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）：2 型神经纤维瘤病 (NF2) 是一种显性遗传性疾病，由蛋白 4.1 超家族成员 Merlin (Schwannomin) 的突变引起。 NF2 的症状通常在成年早期出现，是由双侧前庭神经鞘瘤（导致耳聋）和其他良性肿瘤的形成引起的。尽管我们实验室和其他实验室最近的研究取得了重大进展，但 Merlin 的细胞功能及其在肿瘤抑制中的作用仍然很大程度上未知。识别与 Merlin 相互作用的特定蛋白质和信号转导途径尤其重要，因为这些伙伴可能充当 NF2 疾病表型的遗传修饰剂，并为治疗药物提供潜在靶点。常见的果蝇（果蝇）已被证明是了解发育中生物体背景下基因功能的有用模型系统。因此，该提案的总体目标是检查 Merlin 及其功能伙伴 Expanded 在果蝇中的细胞功能，特别是与 Hippo 途径对细胞增殖的控制有关。在下一个资助期内，我们计划继续研究 Merlin 以及发育中有机体和单个细胞中的扩展功能。具体来说，拟议的实验将： 1) 阐明 Merlin/Expanded 和 HSW 通路之间的功能相互作用。具体来说，我们将检验这样的假设：Expanded 在 Hippo 下游发挥作用，调节转录共激活因子 Yorkie。 2) 了解 Merlin 和 Expanded 在调节质膜受体定位和可用性方面的作用。 3) 检查 Hippo、Salvador、Warts 途径的信号传导对调节细胞表面受体丰度的作用。这些实验有望深入了解 Merlin、Expanded 和 Hippo 通路在调节增殖方面的功能。因此，它们将有助于我们了解人类 NF2、一般肿瘤抑制和致癌作用。此外，所提出的实验应该有助于更好地理解在上皮细胞和神经元中建立专门的膜域的细胞过程。最后，这些研究应有助于研究细胞相互作用在发育过程中控制细胞生长和决定细胞命运的机制。