Role of Survivin in Blood Stem Cell Cycle and Apoptosis

生存素在血液干细胞周期和细胞凋亡中的作用

• 批准号: 7085451
• 负责人: Louis M Pelus
• 金额: $ 33.07万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7085451
• 关键词: MCF7 cell; apoptosis; cell cycle; cell differentiation; cell proliferation; clinical research; confocal scanning microscopy; flow cytometry; green fluorescent proteins; hematopoietic stem cells; human tissue; kinase inhibitor; laboratory mouse; p53 gene /protein; phosphorylation; polymerase chain reaction; protein structure function; survivin

DESCRIPTION (provided by applicant): The inhibitor of apoptosis protein Survivin is overexpressed in most cancers and hematologic malignancies and is an indicator of aggressive disease and poor outcome. Survivin is widely expressed during development but not in most adult tissues, making it an attractive therapeutic target. We were the first to demonstrate that Survivin is expressed and growth factor regulated in normal hematopoietic stem cells (HSC). New evidence from several areas now supports a critical role in preservation of cell viability and maintenance of normal mitosis. This leads to 2 hypotheses. First, Survivin is a normal regulator of HSC and Survivin targeted therapies may have hematologic toxicities. We will modulate Survivin expression in adult mouse HSC using retroviruses and quantitate its effects on hematopoiesis by competitive repopulation following transplantation and its role as a potential oncogene. Second, Survivin is a critical and multifaceted mediator of the cell death versus cell division decisions in HSC and understanding Survivin pathways will identify new therapeutic targets. We will investigate signaling pathways that regulate Survivin production and the molecular/biochemical relationships between Survivin and the intracellular regulators of apoptosis and cell cycle, i.e., cyclins, cyclin dependent kinases (cdks), cdk inhibitors (CDKIs), and the p53 family of tumor suppressors. We will investigate these interactions in normal primary HSC, in novel hematopoietic and nonhematopoietic cell line models, in which Survivin expression/disruption can be transiently or conditionally modulated, and in mice, in which genes for cell cycle and apoptosis related proteins have been deleted. Understanding the hematologic consequence of normal and abnormal Survivin expression and defining the molecular mechanisms of act of Survivin in regulating cell survival, cell cycle progression, and cell division in normal HSC will provide important information on normal cell survival and cell cycle regulation critical to the design of safe and efficacious Survivin-based therapies that target cell cycle and apoptosis.

描述（由申请人提供）：凋亡抑制蛋白Survivin在大多数癌症和恶性血液病中过表达，是侵袭性疾病和不良结局的指标。生存素在发育过程中广泛表达，但在大多数成人组织中不表达，使其成为有吸引力的治疗靶点。我们是第一个证明Survivin在正常造血干细胞（HSC）中表达和生长因子调节的人。来自几个领域的新证据现在支持在保存细胞活力和维持正常有丝分裂中的关键作用。这导致了两个假设。首先，Survivin是HSC的正常调节因子，Survivin靶向治疗可能具有血液学毒性。我们将使用逆转录病毒调节存活素在成年小鼠HSC中的表达，并通过移植后的竞争性再增殖来定量其对造血的影响及其作为潜在癌基因的作用。其次，Survivin是HSC中细胞死亡与细胞分裂决定的关键和多方面的介导者，了解Survivin途径将确定新的治疗靶点。我们将研究调节Survivin产生的信号通路以及Survivin与细胞凋亡和细胞周期的细胞内调节因子之间的分子/生物化学关系，即，细胞周期蛋白、细胞周期蛋白依赖性激酶（cdk）、cdk抑制剂（CDKIs）和肿瘤抑制剂的p53家族。我们将研究这些相互作用在正常的初级HSC，在新的造血和非造血细胞系模型，其中生存素表达/中断可以暂时或有条件地调制，并在小鼠中，其中细胞周期和凋亡相关蛋白的基因已被删除。了解正常和异常Survivin表达的血液学后果，并确定Survivin在正常HSC中调节细胞存活、细胞周期进程和细胞分裂的分子机制，将提供关于正常细胞存活和细胞周期调节的重要信息，这些信息对于设计安全有效的靶向细胞周期和凋亡的基于Survivin的疗法至关重要。