The Role of ABC Transporters in Stem Cells

ABC 转运蛋白在干细胞中的作用

• 批准号: 7102654
• 负责人: Brian P Sorrentino
• 金额: $ 36.62万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102654
• 关键词: animal tissue; biomarker; bone marrow; cell growth regulation; cell population study; cell sorting; clinical research; gene expression; genetic transcription; genetically modified animals; hematopoietic stem cells; human subject; laboratory mouse; membrane transport proteins; myelogenous leukemia; neoplasm /cancer diagnosis; neoplastic cell; neuroblastoma; protein structure function; tissue /cell culture

DESCRIPTION (provided by applicant): The overall goal of this research proposal is to further define the role of the Abcg2 transporter in hematopoietic stem cells (HSCs), in stem cells from other non-hematopoietic organs, and in cancer stem cells. Work in the prior funding period has shown that: 1) Abcg2 expression is required for the side population (SP) phenotype in HSCs and serves as a prospective molecular marker for isolating HSCs, 2) Abcg2-expressing SP cells exist in skeletal muscle, and as demonstrated by other labs, in many other non-hematopoietic organs, 3) a majority of human AML samples contain a small subpopulation of ABCG2-expressing cells that could represent a leukemia stem cell population, and 4) expression of Abcg2 protects HSCs from mitoxantrone, a xenobiotic drug. Experiments are now planned that will unequivocally determine whether Abcg2-expressing cells have stem cell activity in skeletal muscle and in other organ systems. By using a novel genetic approach, we will track the progeny of Abcg2-expressing cells in mice at different stages of development in order to evaluate candidate organ systems for the presence of Abcg2-expressing stem cells. A second aim is to use monoclonal antibodies to isolate hematopoietic stem cells from human and non-human primates. Using a panel of monoclonal antibodies that recognize external epitopes on ABCG2 that are present on living cells, we will isolate cells expressing ABCG2 and test them for hematopoietic stem cell function, with the ultimate goal defining a new stem cell population for use in transplantation protocols. Lastly, we will evaluate whether Abcg2 expression can identify cancer stem cells in myelogenous leukemia and in neuroblastoma. Both tumors contain a subpopulation of cells that express the side population phenotype and ABCG2, and therefore may represent a cancer stem cell population. We have and will develop novel genetic mouse models that should allow us to test this hypothesis in an unequivocal fashion. Not only could this provide a new marker for cancer stem cells, but it would have prognostic and therapeutic significance for these human cancers. Altogether, these studies should further elucidate the role of the Abcg2 transporter in normal and malignant stem cells, and should further increase our understanding of the role of ABC transporters in stem cells.

描述（由申请人提供）：这项研究建议的总体目标是进一步定义ABCG2转运蛋白在造血干细胞中的作用，在其他非造血器官的干细胞中以及癌症干细胞中的干细胞中的作用。先前的资金期间的工作表明：1）HSC中侧种群（SP）表型需要ABCG2表达，并用作隔离HSC的前瞻性分子标记，2）骨骼肌中存在ABCG2表达的SP细胞，如许多其他非甲状腺肿瘤的人类杂物，在许多其他非甲状腺瘤中所证明的，这是一个较小的人类的三个次数，其中一个较小的人类属于3）。表达ABCG2的细胞，可以代表白血病干细胞群体，而4）ABCG2的表达可保护HSC免受异种生物药物Mitoxantrone的影响。现在计划实验，将明确确定表达ABCG2的细胞在骨骼肌和其他器官系统中是否具有干细胞活性。通过使用一种新的遗传方法，我们将在不同发育阶段在小鼠中跟踪小鼠表达ABCG2细胞的后代，以评估候选器官系统的表达干细胞。第二个目的是使用单克隆抗体将造血干细胞与人类和非人类灵长类动物分离。使用一组识别存在于活细胞上ABCG2上外部表位的单克隆抗体，我们将分离表达ABCG2的细胞并测试它们是否有造血干细胞功能，其最终目标定义了新的干细胞种群，以用于移植方案中。最后，我们将评估ABCG2表达是否可以鉴定髓质白血病和神经母细胞瘤中的癌症干细胞。两种肿瘤都包含表达侧种群表型和ABCG2的细胞亚群，因此可能代表癌症干细胞群体。我们已经并且将开发新的遗传小鼠模型，这应该使我们能够以明确的方式检验这一假设。这不仅可以为癌症干细胞提供一个新的标记，而且对这些人类癌症具有预后和治疗意义。总而言之，这些研究应进一步阐明ABCG2转运蛋白在正常和恶性干细胞中的作用，并应进一步增强我们对ABC转运蛋白在干细胞中的作用的理解。