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

• 批准号: 9133479
• 负责人: Soma Sengupta
• 金额: $ 18.22万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9133479
• 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; Early treatment; Electrophysiology (science); Electroporation; Embryo; Exhibits; Faculty; Family; GABA-A Receptor; Genetic Transcription; Genomics; Hospitals; Human; Impaired cognition; Knowledge; Laser Scanning Microscopy; Lipids; MYC Gene Amplification; Maintenance; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant neoplasm of brain; Mass Spectrum Analysis; Mediating; Mentors; Metabolic; Methodology; Molecular; Molecular Diagnosis; Morbidity - disease rate; Mus; National Institute of Neurological Disorders and Stroke; Neoplasm Metastasis; Neurotransmitter Receptor; Normal Cell; Oncogenes; Operating Rooms; Operative Surgical Procedures; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Peptides; Phenotype; Photoreceptors; Proteomics; Publications; Radiation; Radiation-Sensitizing Agents; Refractory; Regulation; Relapse; Research; Research Personnel; Resistance; Resource Sharing; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Slice; Survival Rate; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Transgenic Mice; Transgenic Organisms; Tumor Tissue; Woman; Work; Xenograft procedure; base; biomarker identification; chemotherapy; conventional therapy; gamma-Aminobutyric Acid; genomic profiles; improved; in utero; individualized medicine; insight; killings; knock-down; medulloblastoma; medulloblastoma cell line; molecular subtypes; mortality; mouse model; nerve stem cell; neurosurgery; new therapeutic target; novel; overexpression; pineoblastoma; public health relevance; rapid detection; receptor; response; stem; targeted biomarker; therapeutic target; tool; tumor; tumor growth

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儿童恶性脑肿瘤，也是儿童癌症相关死亡的重要原因。在髓母细胞瘤治疗中幸存下来的儿童往往严重认知障碍，并依赖于他们的家人继续照顾。这些亚型之一，即组3，具有癌基因（MYC）、光感受器和称为GABRA 5的GABA-A神经递质受体的高水平表达。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%;而只有20%的第3组肿瘤患者尽管接受了最大限度的治疗，包括手术，放疗和化疗，但仍存活。因此，对治疗这些治疗抗性患者的治疗策略存在显著需求。虽然神经递质受体在正常细胞中已被很好地定义，但它们在脑肿瘤的维持和进展中的重要性尚不清楚，并且靶向这些受体在脑癌中的作用尚未探索。在我最近的出版物中，一种对GABRA 5高度特异的新型苯二氮卓衍生物已被证明在细胞培养和小鼠模型中均可有效杀死第3组髓母细胞瘤。源于我之前的NINDS R25研究，我作为BIDMC的初级教师和首席研究员的4年K 08项目将如下：查看由于GABRA 5信号传导导致的DNA损伤;研究正常小脑和髓母细胞瘤发育中的GABRA 5;并通过组织质谱检测参与GABRA 5信号传导的信号分子。此外，组织质谱法正在布里格姆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。它还没有被测试为髓母细胞瘤，我们的 希望能快速诊断出髓母细胞瘤的亚型，以便为儿童提供量身定制的治疗，从而减少对儿童的治疗毒性。我将成为K 08奖的单人练习生。