Elucidating Signaling Pathways for GABA-A Receptor Alpha5 in an Aggressive Subtype of Medulloblastomas

阐明侵袭性髓母细胞瘤亚型中 GABA-A 受体 Alpha5 的信号通路

基本信息

批准号：
8820417
负责人：
Soma Sengupta
金额：
$ 18.48万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8820417
关键词：
Address Agar Agonist Apoptosis Award Benzodiazepines Biochemical Biological Markers Brain Brain Neoplasms Cancer Etiology Caring Cell Culture Techniques Cell Death Cells Chemicals Child Childhood Malignant Brain Tumor Cisplatin Clinical Trials DNA Damage Development Diagnosis Drug Targeting Early treatment Electroporation Embryo Exhibits Faculty Family GABA-A Receptor Genomics Hospitals Human Impaired cognition Knowledge Laser Scanning Microscopy Lead Lipids MYC Gene Amplification Maintenance Malignant - descriptor Malignant neoplasm of brain Mass Spectrum Analysis Mediating Mentors Metabolic Methodology Molecular Morbidity - disease rate Mus National Institute of Neurological Disorders and Stroke Neurons Neurotransmitter Receptor Normal Cell Oncogenes Operating Rooms Outcome Pathway interactions Patients Peptides Phenotype Photoreceptors Proteomics Publications Radiation Radiation-Sensitizing Agents Radiosurgery Refractory Regulation Relapse Research Research Personnel Resistance Resource Sharing Role Signal Pathway Signal Transduction Signaling Molecule Slice Staging Survival Rate Techniques Testing Therapeutic Tissues Toxic effect Transgenic Mice Transgenic Organisms Tumor Tissue Woman Work Xenograft procedure base chemotherapy gamma-Aminobutyric Acid improved in utero insight killings medulloblastoma medulloblastoma cell line mortality mouse model neurosurgery new therapeutic target novel overexpression pineoblastoma public health relevance rapid detection receptor response stem tool tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Medulloblastoma is the most common malignant pediatric brain tumor and a significant cause of cancer-related mortality in children. Children surviving medulloblastoma treatments are often severely cognitively impaired and are dependent on their families for continuing care. One of these subtypes, namely Group 3, has high levels of expression of an oncogene (MYC), photoreceptors, and a GABA-A neurotransmitter receptor called GABRA5. For other subtypes, survival of patients with effectively treated medulloblastoma exceeds 70%; while only 20% of patients who have Group 3 tumors survive despite receiving maximal treatment that includes surgery, radiation and chemotherapy. There is therefore a significant demand for therapeutic strategies to treat these treatment-resistant patients. Although neurotransmitter receptors have been well defined in normal cells, their importance in the maintenance and progression of brain tumors is unknown and the effect of targeting these receptors in brain cancers is unexplored. In my recent publication, a novel benzodiazepine derivative that is highly specific for GABRA5, has been shown to be effective in killing Group 3 medulloblastomas, both in cell culture and in the mouse model. Stemming from my prior NINDS R25 research, my 4 year K08 project as junior faculty and principal researcher at the BIDMC will be as follows: to look at DNA damage due to GABRA5 signaling; studying GABRA5 in normal cerebellar and medulloblastoma development; and detecting signaling molecules involved in GABRA5 signaling by tissue mass spectrometry. In addition, tissue mass spectrometry is being piloted in the neurosurgery operating room at the Brigham and Women's Hospital to try and diagnose subtypes of brain tumors rapidly, which would be highly beneficial for clinical trials. It has not been tested for medulloblastoma, and our hope is to diagnose the subtype of medulloblastoma rapidly so as to tailor the treatment that a child receives, thereby reducing treatment toxicity to the child. I would be the solo trainee of ths K08 award.

描述（由申请人提供）：髓母细胞瘤是最常见的恶性儿童脑肿瘤，也是儿童癌症相关死亡的重要原因。髓母细胞瘤治疗后幸存的儿童通常患有严重的认知障碍，并且依赖家人的持续护理。其中一种亚型（即第 3 组）具有高水平的癌基因 (MYC)、光感受器和称为 GABRA5 的 GABA-A 神经递质受体表达。对于其他亚型，有效治疗的髓母细胞瘤患者的生存率超过70%；尽管接受了包括手术、放疗和化疗在内的最大程度的治疗，但只有 20% 的第 3 组肿瘤患者能够存活。因此，迫切需要治疗这些耐药患者的治疗策略。尽管神经递质受体在正常细胞中已被明确定义，但它们在脑肿瘤维持和进展中的重要性尚不清楚，并且尚未探索针对脑癌中这些受体的作用。在我最近发表的文章中，一种对 GABRA5 具有高度特异性的新型苯二氮卓衍生物已被证明可以在细胞培养物和小鼠模型中有效杀死第 3 组髓母细胞瘤。源于我之前的 NINDS R25 研究，我作为 BIDMC 初级教师和首席研究员的 4 年 K08 项目将如下：观察 GABRA5 信号传导引起的 DNA 损伤；研究正常小脑和髓母细胞瘤发育中的 GABRA5；并通过组织质谱检测参与GABRA5信号传导的信号分子。此外，组织质谱法正在布莱根妇女医院的神经外科手术室进行试点，以尝试快速诊断脑肿瘤的亚型，这对临床试验非常有益。尚未针对髓母细胞瘤进行测试，我们的希望能够快速诊断髓母细胞瘤的亚型，以便为儿童制定治疗方案，从而减少治疗对儿童的毒性。我将成为K08奖的独唱练习生。