Cell Death and Clonal Survival in Myelodysplastic Syndr*

骨髓增生异常综合征中的细胞死亡和克隆存活*

基本信息

批准号：
7487816
负责人：
H. JOACHIM DEEG
金额：
$ 41.01万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-15 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7487816
关键词：
Affect Age Aging Apoptosis Apoptotic Categories Cell Death Cell Line Cell Survival Cell Transplants Cells Cessation of life Chronic Clinical Clonal Expansion Complex Count Data Defective spinal cord development Disease Disease Progression Dysmyelopoietic Syndromes Elevation Event Frequencies Functional disorder Gene Expression Genetic Hematopoiesis Hematopoietic Hematopoietic stem cells Human Immunodeficient Mouse In Vitro Incidence Individual Inflammatory Intervention Karyotype Marrow Mediating Modeling Modification Molecular Target Mononuclear Mus Myeloid Cells NF-kappa B Patients Pattern Play Population Process Protein Overexpression Quality of life Regulation Role Signal Pathway Signal Transduction Stromal Cells System Techniques Testing Transplantation Tumor Necrosis Factor-alpha Tumor Necrosis Factors cell stroma cytokine human TNF protein improved in vitro Assay in vivo in vivo Model myeloblast novel novel therapeutics prevent

项目摘要

DESCRIPTION (provided by applicant): The Myelodysplastic Syndrome (MDS) is predominantly a disease of older age, and with the aging of the population, an increase in cases is expected. Our proposal is aimed at improving our understanding of the pathophysiology of MDS, and to identify cellular or molecular targets suitable for novel treatment strategies. MDS is a clonal disorder of hematopoietic stem cells; however, there is evidence that factors in the microenvironment contribute to the propagation of the disease. Thus, we propose to characterize interactions between the marrow microenvironment and hematopoietic precursors and identify signaling pathways that determine programmed cell death (apoptosis) and clonal survival. Specifically, we will 1) define stroma-dependent activities that affect survival/expansion of clonal and non-clonal hematopoietic precursors from MDS marrow. In an in vitro system using myeloid cell lines and primary MDS cells, we will characterize the functional relevance of tumor necrosis factor (TNF)alpha-induced alterations in gene expression in stroma for the support of clonal or non-clonal hematopoietic precursors (TNFalpha is upregulated in MDS). In a xenogeneic in vivo model we will determine the role of human stroma for the survival of MDS-derived clones transplanted into mice. We will 2) characterize apoptotic and proliferative events in MDS marrow and correlate these with disease progression. We will define interactions of TNFalpha-initiated signals that control apoptosis and proliferation, in particular, the roles of NFkappaB and the anti-apoptotic molecule, FLIP. Preliminary in vitro data show that overexpression of FLIP enhances cell survival. We will now determine in vivo whether genetic modification of FLIP expression in MDS cells transplanted in immunodeficient mice affects survival and allows for expansion of the clone. The techniques involved in pursuit of our objectives include in vitro assays of hematopoiesis, apoptosis, and proliferation in in vitro culture systems. The relevance of in vitro findings will be validated in vivo in a xenogeneic transplant model of cell lines and primary MDS cells in immunodeficient mice in which propagation of normal and clonal cells will be characterized. By using interventions that block relevant signals or by genetically modifying molecules that play pivotal roles, we will identify potential targets for novel therapeutic strategies. The human population is aging, and the incidence of MDS increases with age. Novel treatment approaches are needed that are tolerated by older individuals and, hopefully, will not interfere with their quality of life. To achieve these objectives, we must better understand the underlying mechanisms of MDS and thereby identify ways by which the disease process can be arrested, progression prevented, and the disease hopefully be cured.

描述（由申请人提供）：骨髓增生性综合征（MDS）主要是年龄较大的疾病，随着人口的老龄化，预计病例会增加。我们的建议旨在提高我们对MD的病理生理学的理解，并确定适合新型治疗策略的细胞或分子靶标。 MDS是造血干细胞的克隆疾病。但是，有证据表明，微环境中的因素有助于疾病的传播。因此，我们建议表征骨髓微环境和造血前体之间的相互作用，并确定确定程序性细胞死亡（凋亡）和克隆存活率的信号传导途径。具体而言，我们将1）定义基质依赖性活性，这些活性影响了MDS骨髓的克隆和非克隆造血前体的存活/膨胀。在使用髓样细胞系和原代MDS细胞的体外系统中，我们将表征肿瘤坏死因子（TNF）α诱导基因表达中基因表达的变化的功能相关性，以支持克隆或非锁骨血肿前体的支持（TNFALPHA在MDS中上调）。在异构体内模型中，我们将确定人基质在移植到小鼠中的MDS衍生克隆存活中的作用。我们将2）表征MDS骨髓中的凋亡和增殖事件，并将其与疾病进展相关。我们将定义tnfalpha引起的信号的相互作用，这些信号控制着凋亡和增殖，特别是NFKAPPAB和抗凋亡分子的作用，Flip。初步的体外数据表明，翻转的过表达可增强细胞存活。现在，我们将在体内确定在免疫缺陷小鼠中移植的MDS细胞中FLIP表达的遗传修饰是否会影响存活并允许克隆的扩展。追求我们目标的技术包括体外造血，凋亡和体外培养系统中增殖的测定。体外发现的相关性将在体内验证在免疫缺陷小鼠中的细胞系和原代MDS细胞的异构移植模型中，其中将表征正常细胞和克隆细胞的传播。通过使用阻断相关信号或通过基因修饰发挥关键作用的分子的干预措施，我们将确定新型治疗策略的潜在靶标。人口正在衰老，MDS的发病率随着年龄的增长而增加。需要新颖的治疗方法，这些方法被老年人所容忍的，希望不会干扰其生活质量。为了实现这些目标，我们必须更好地理解MDS的潜在机制，从而确定可以逮捕疾病过程，预防进展并希望治愈疾病的方法。