Nicotinic acetylcholine receptors and neuroblastoma

烟碱乙酰胆碱受体与神经母细胞瘤

基本信息

批准号：
8326061
负责人：
Rae Nishi
金额：
$ 22.88万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8326061
关键词：
Abdomen Accounting Adolescent Adrenal Medulla Age Aspirate substance Automobile Driving Autonomic nervous system Binding Biological Assay Blood - brain barrier anatomy Bone Growth Bone Marrow Bone Marrow Cells Bone Marrow Transplantation Canada Cell Line Cell Proliferation Cells Cessation of life Chest Child Data Disease Drug Delivery Systems Future Genes Goals Home environment Human Immunodeficient Mouse In Vitro Infant Lentivirus Vector Liver Malignant - descriptor Malignant Neoplasms Metastatic malignant neoplasm to brain Mus Names Neoplasm Metastasis Neural Crest Neuroblastoma Neurons Nicotinic Receptors Patients Pediatric Hospitals Pediatric Oncology Pediatrics Pharmaceutical Preparations Phenotype Preclinical Drug Evaluation Primary Neoplasm Proliferating RNA Interference Radiation Regimen Reporting Resistance Site Skin Spinal Cord Staging Stem cells Sympathetic Ganglia Testing Transcript Tumor Cell Line Tumor-Derived Tumorigenicity Vermont Xenograft procedure base cancer genomics cancer therapy chemotherapy gene discovery high throughput screening in vivo killings malignant phenotype nerve stem cell neuroblastoma cell new therapeutic target novel novel therapeutics oncology outcome forecast overexpression precursor cell progenitor receptor self-renewal tumor tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Neuroblastoma is a cancer arising from autonomic neuron progenitor cells that occurs in the adrenal medulla or as paraspinal tumors in the abdomen or thorax of infants and young children. If it is identified in children over the age of 1, it is nearly always a highly malignant, aggressive cancer that kills the child within 4-5 years, even after a strenuous chemotherapeutic regimen combined with radiation and a bone marrow transplant. This project will determine whether an unusual nicotinic acetylcholine receptor is a novel target for therapeutics in treating neuroblastoma. We have isolated cells from bone marrow aspirates obtained from patients with stage 4 neuroblastoma. When tested in xenograft assays in immunodeficient mice, the cells can be categorized into tumor-initiating cells (TICs) and non-tumor initiating cells (non-TICs). We have discovered that the gene encoding the a5 nicotinic acetylcholine receptor (nAChR) subunit, CHRNA5, is expressed at 7- 19-fold higher levels in TICs than in non-TICs. Furthermore, CHRNA5 is 2-10-fold higher in TICs than in normal neurogenic neural crest stem cells, and CHRNA5 is elevated in primary neuroblastoma tumors and cell lines derived from tumors (SH-SY5Y, SKN-KCN, SKN-KCNR) above levels found in normal sympathetic ganglia. In a high throughput drug screen for compounds that would reduce proliferation of TICs, MG 624, a nAChR antagonist, was identified. Based upon our expression data, we hypothesize that nicotinic receptors containing a5 contribute to the malignant phenotype of neuroblastoma and therefore may be a new target for drugs because these receptors are uncommon in the normal autonomic nervous system. The proposed aims will test this hypothesis by: 1) using RNAi to determine whether one or more nAChR subunits is necessary for the malignant phenotype of neuroblastoma cells (TICs and cell lines from primary tumors) and their sensitivity to MG 624; 2) determining whether overexpression of CHRNA5 and/or other subunits in normal skin-derived precursors is sufficient to produce a transformed phenotype.

描述（由申请人提供）：神经母细胞瘤是由肾上腺髓质中发生的自主神经元祖细胞引起的癌症，或作为婴儿和幼儿的腹部或胸腔中的副脊髓肿瘤。如果在1岁以上的儿童中确定它，它几乎总是一种高度恶性的，侵略性的癌症，即使经过剧烈的化学治疗方案，也可以在4 - 5年内杀死儿童，并结合了放射线和骨髓移植。该项目将确定异常的烟碱乙酰胆碱受体是否是治疗神经细胞瘤治疗的新靶标。我们从4期神经母细胞瘤患者获得的骨髓抽吸物中分离出细胞。当在免疫缺陷型小鼠中进行异种移植分析进行测试时，可以将细胞分为肿瘤发射细胞（TICS）和非肿瘤启动细胞（非TICS）。我们已经发现，编码A5烟碱乙酰胆碱受体（NACHR）亚基ChRNA5的基因在TICS的水平高7-19倍以上。此外，TICS的CHRNA5比正常神经源性神经rest干细胞高2-10倍，并且在原代神经母细胞瘤肿瘤中CHRNA5升高，并且在正常的交感神经神经节中发现的原发性神经母细胞瘤肿瘤和来自肿瘤（SH-SY5Y，SKN-KCN，SKN-KCNR）的细胞系升高。在高吞吐药物筛选中，可以鉴定出降低TICS增殖的化合物，Mg 624，一种NACHR拮抗剂。根据我们的表达数据，我们假设含有A5的烟碱受体有助于神经母细胞瘤的恶性表型，因此可能是药物的新靶标，因为这些受体在正常的自主神经系统中并不常见。提出的目的将通过以下方式检验以下方法：1）使用RNAi来确定一个或多个NACHR亚基是否对于神经母细胞瘤细胞的恶性表型（来自原发性肿瘤的TICS和细胞系）及其对Mg 624的敏感性是否必需。 2）确定正常皮肤衍生前体中CHRNA5和/或其他亚基的过表达是否足以产生转化的表型。