ABC Transporters in Human Disease and Multidrug Resistan

人类疾病和多重耐药性中的 ABC 转运蛋白

• 批准号: 7038634
• 负责人: MICHAEL DEAN
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7038634
• 关键词: Tunicata; alternatives to animals in research; chemotherapy; frameshift mutation; gene expression; gene mutation; genetic disorder; genetic mapping; genetic models; histology; membrane transport proteins; multidrug resistance; neoplasm /cancer genetics; point mutation; respiratory disorder; respiratory epithelium; secretion; zebrafish

The ATP-binding cassette (ABC) gene family encodes a diverse group of transporter proteins that pump a wide variety of compounds across the membranes of cells and tissues. Several human ABC transporters are overexpressed in tumor cells that are resistant to chemotherapy drugs. There are 48 ABC genes in the human genome and 16 of these are mutated in genetic diseases affecting the eye, liver, cholesterol transport and other functions. We have demonstrated that the ABCA3 gene is mutated in children with neonatal respiratory failure. These patients have defects in the production of lung surfactant, a lipid rich secretion produced by alveolar type II cells. These patients are either homozygous or compound heterozygous for mutations in the gene. The mutations identified include frame shift, nonsense and point mutations in conserved residues. Ultramicroscopic analysis of lung tissue from these patients shows abnormal lamellar bodies in the alveolar cells. Mildly affected patients were identified that have missense mutations that may be partially functional. Thus mutations in the ABCA3 gene may be involved in other respiratory diseases. Further characterization of this gene should yield insights into surfactant secretion and lung function. We have characterized the ABC genes in the zebrafish and the tunicate Ciona, both of which are excellent model organisms for studying gene expression and function. The zebrafish has conserved 32 of the 48 human ABC genes including several such as ABCC6 that cause human disease but whose function is unknown.

ATP结合盒（ABC）基因家族编码了各种各样的转运蛋白，这些蛋白会在细胞和组织的整个膜上泵送各种化合物。几种人类ABC转运蛋白在抗化疗药物具有抗性药物中过表达。人类基因组中有48个ABC基因，其中16个在影响眼睛，肝脏，胆固醇转运和其他功能的遗传疾病中被突变。我们已经证明，新生儿呼吸衰竭儿童中ABCA3基因已突变。这些患者在肺表面活性剂的产生中存在缺陷，肺表面活性剂是由肺泡II型细胞产生的富脂质分泌。这些患者是基因突变的纯合子或复合杂合子。确定的突变包括保守残基中的框架移位，胡说八道和点突变。对这些患者的肺组织的超显微镜分析显示肺泡细胞中的层状体异常。鉴定出有可能部分功能性的错义突变的患者。因此，ABCA3基因中的突变可能与其他呼吸道疾病有关。该基因的进一步表征应产生对表面活性剂分泌和肺功能的见解。我们已经表征了斑马鱼和剪裁ciona中的ABC基因，这两者都是用于研究基因表达和功能的出色模型生物。斑马鱼保存了48个人类ABC基因中的32个，其中包括几种引起人类疾病但其功能未知的ABCC6。