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Contribution of c-Jun N-terminal kinase activity to vestibular schwannoma growth

c-Jun N 末端激酶活性对前庭神经鞘瘤生长的贡献

基本信息

批准号：
8509646
负责人：
Marlan R Hansen
金额：
$ 34.14万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8509646
关键词：
1-Phosphatidylinositol 3-Kinase Acoustic Neuroma Address Adenoviruses Alternative Therapies Antibodies Apoptosis Biological Assay Brain Stem Cell Culture Techniques Cell Death Cell Proliferation Cell Survival Cells Clinical DNA Damage Data Deoxyuridine Development Dominant-Negative Mutation Elements Excision Facial paralysis Gene Transfer Goals Growth Growth Factor Health Human Image Immunofluorescence Immunologic Implant Intracranial Neoplasms JUN gene Label Lead Link MAPK8 gene MAPK9 gene MEKs Magnetic Resonance Imaging Mediating Microsurgery Mitochondria Mitogen-Activated Protein Kinases Modeling Morbidity - disease rate Mutate Mutation N-terminal Nerve Growth Factors Neuregulins Neurilemmoma Neurofibromin 2 Nude Mice Oligonucleotides Oxidative Stress Patients Phosphotransferases Protein Isoforms Proteins Proto-Oncogene Proteins c-akt RNA Interference Radiation Tolerance Radiation therapy Radioresistance Radiosurgery Reactive Oxygen Species Resistance SP600125 Schwann Cells Signal Transduction Superoxides Testing Therapeutic Tinnitus Transgenic Mice Tumor Suppressor Genes Vestibular Nerve Viral Western Blotting Xenograft procedure cell growth cell killing cytotoxic cytotoxicity deafness enzyme activity extracellular hearing impairment human MAP3K1 protein insight irradiation kinase inhibitor neural growth novel overexpression prevent relating to nervous system research study response rho GTP-Binding Proteins stress-activated protein kinase 1 therapeutic target tumor tumor growth tumorigenesis uptake

项目摘要

DESCRIPTION (provided by applicant): Vestibular schwannomas (VSs) develop from the Schwann cells (SCs) of the vestibular nerve. They cause significant morbidity including deafness, tinnitus, facial paralysis, imbalance, and brainstem compression. Microsurgical removal and stereotactic radiosurgery/stereotactic radiotherapy (SRS/SRT) constitute the only current treatments for VSs and often result in deafness, tinnitus, facial paralysis and imbalance themselves. Further, some patients that require treatment are not good candidates for either microsurgery or SRS/SRT. Development of effective alternative therapies will be of great benefit to those patients unsuitable for current therapeutic options. Understanding the factors that contribute to VS tumorigenesis and radiosensitivity will help identify potential therapeutic targets. Merlin, the defective gene product in VSs, regulates the activity of kinases implicated in tumorigenesis including extracellular regulated kinases (ERKs), phosphatidylinositol-3-kinase (PI3-K)/Akt, and c-Jun N-terminal kinases (JNKs). Preliminary data demonstrate activation of ERKs and PI-3K/Akt in VS cells leading to increased proliferation and activation of JNK promoting cell proliferation and survival. Inhibition of JNK activity increases accumulation of reactive oxygen species (ROS), including mitochondrial superoxides. Further ROS scavengers prevent apoptosis in VS cells with suppressed JNK, implying that the prosurvival effects of JNK may be due to its ability to reduce oxidative stress. Conversely, JNK activity appears to promote apoptosis in denervated SCs. Finally, VS cells appear highly resistant to irradiation (IR). These observations lead to the hypothesis that loss of merlin function in VS cells results in persistent JNK activation which, in turn, suppresses accumulation of ROS, promotes cell survival, and confers radioresistance. The goal of these studies is to test this hypothesis in primary human VS cell cultures and human VS xenografts implanted in nude mice. The first aim is to determine whether merlin inhibits JNK activity in human VS cells and in SCs and identify the upstream signaling leading to JNK activation. This will be addressed by replacing functional merlin into VS cells using viral-mediated gene transfer and determining if JNK activity is consequently suppressed. Parallel studies will ask if SCs derived from transgenic mice lacking functional merlin demonstrate increased JNK activity. The second aim will use primary human VS cultures and orthotopic xenografts in nude mice to determine the extent to which persistent JNK activity promotes VS growth by increasing cell proliferation and survival. The third aim seeks to determine if suppression of specific reactive oxygen species (ROS) by JNK contributes to VS cell survival and the final aim seeks to determine whether JNK inhibitors potentiate the ability of 3-irradiation (IR) to induce VS cell apoptosis and reduce proliferation. The results of these studies will provide insights into the fundamental mechanisms contributing to VS cell growth and radiosensitivity and will likely contribute to the development of novel therapies for VSs.

描述(申请人提供)：前庭神经鞘瘤(VSS)起源于前庭神经的雪旺细胞(SCs)。它们会导致严重的发病率，包括耳聋、耳鸣、面瘫、失衡和脑干受压。显微手术切除和立体定向放射外科/立体定向放射治疗(SRS/SRT)是目前治疗VSS的唯一方法，通常会导致耳聋、耳鸣、面瘫和自身失衡。此外，一些需要治疗的患者既不适合显微手术，也不适合SRS/SRT。开发有效的替代疗法将对那些不适合当前治疗方案的患者大有裨益。了解影响肿瘤发生和放射敏感性的因素将有助于确定潜在的治疗靶点。Merlin是VSS中的缺陷基因产物，它调节与肿瘤发生有关的各种蛋白的活性，包括细胞外调节蛋白(ERKs)、磷脂酰肌醇-3-激酶(PI3-K)/Akt和c-jun氨基末端蛋白(JNKs)。初步数据表明，VS细胞中ERKs和PI-3K/Akt的激活导致细胞增殖增加，而JNK的激活促进细胞的增殖和存活。抑制JNK活性会增加活性氧物种(ROS)的积累，包括线粒体超氧化物。此外，ROS清除剂通过抑制JNK抑制VS细胞的凋亡，暗示JNK的生存效应可能是由于其降低氧化应激的能力所致。相反，JNK活性似乎促进失神经干细胞的凋亡。最后，VS细胞表现出对辐射(IR)的高度抵抗。这些观察结果导致了一种假设，即VS细胞中Merlin功能的丧失导致JNK持续激活，进而抑制ROS的积累，促进细胞存活，并赋予辐射抗性。这些研究的目的是在原代人类VS细胞培养和人VS裸鼠体内移植的异种移植中检验这一假设。第一个目的是确定Merlin是否抑制人VS细胞和SCs中的JNK活性，并确定导致JNK激活的上游信号。这将通过使用病毒介导的基因转移将功能性Merlin替换到VS细胞中并确定JNK活性是否因此而被抑制来解决。平行研究将询问缺乏功能性Merlin的转基因小鼠的干细胞是否显示出JNK活性增加。第二个目标将使用原代人VS培养和裸鼠原位异种移植来确定持续的JNK活性通过增加细胞增殖和存活而促进VS生长的程度。第三个目的是确定JNK对特定的活性氧物种(ROS)的抑制是否有助于VS细胞的存活，最终目的是确定JNK抑制剂是否增强3-射线(IR)诱导VS细胞凋亡和抑制增殖的能力。这些研究的结果将为深入了解VS细胞生长和辐射敏感性的基本机制提供帮助，并可能有助于VSS新疗法的开发。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Influence of cAMP and protein kinase A on neurite length from spiral ganglion neurons.

DOI：
10.1016/j.heares.2011.11.010
发表时间：
2012-01
期刊：
HEARING RESEARCH
影响因子：
2.8
作者：
Xu, Ningyong;Engbers, Jonathan;Khaja, Sobia;Xu, Linjing;Clark, J. Jason;Hansen, Marlan R.
通讯作者：
Hansen, Marlan R.

Surgical management of internal auditory canal and cerebellopontine angle facial nerve schwannoma.