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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）：神经母细胞瘤是一种由自主神经元祖细胞引起的癌症，发生在肾上腺髓质或婴幼儿腹部或胸部的脊柱旁肿瘤。如果在1岁以上的儿童中发现，它几乎总是一种高度恶性的、侵袭性的癌症，即使在经过艰苦的化疗方案、放疗和骨髓移植后，也会在4-5年内导致儿童死亡。该项目将确定一种不寻常的烟碱乙酰胆碱受体是否是治疗神经母细胞瘤的新靶点。我们从4期神经母细胞瘤患者的骨髓抽吸中分离出细胞。在免疫缺陷小鼠的异种移植试验中，细胞可分为肿瘤启动细胞（TICs）和非肿瘤启动细胞（non-TICs）。我们发现编码a5烟碱乙酰胆碱受体（nAChR）亚基的基因CHRNA5在tic中的表达水平比非tic高7- 19倍。此外，CHRNA5在tic中的表达比正常神经源性神经嵴干细胞高2-10倍，并且CHRNA5在原发性神经母细胞瘤肿瘤和肿瘤衍生细胞系（SH-SY5Y, SKN-KCN, SKN-KCNR）中的表达高于正常交感神经节中的水平。在高通量药物筛选中，发现了一种nAChR拮抗剂mg624。根据我们的表达数据，我们假设含有a5的尼古丁受体有助于神经母细胞瘤的恶性表型，因此可能成为药物的新靶点，因为这些受体在正常的自主神经系统中并不常见。我们提出的目标将通过以下方法来验证这一假设：1)使用RNAi来确定一个或多个nAChR亚基是否对神经母细胞瘤细胞（tic和原发肿瘤细胞系）的恶性表型及其对MG 624的敏感性是必要的；2)确定正常皮肤源性前体中CHRNA5和/或其他亚基的过表达是否足以产生转化表型。