Role of FA proteins in hematopoiesis

FA 蛋白在造血中的作用

• 批准号: 8452195
• 负责人: QISHEN PANG
• 金额: $ 35.93万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-05 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8452195
• 关键词: Acute Myelocytic Leukemia; Adult; Affect; Antioxidants; Apoptosis; Biochemical Genetics; Blood Cells; Cell Proliferation; Cell Survival; Cell physiology; Cells; Child; Childhood; Clinical; Complex; DNA; Development; Disease; Disease Progression; Dysmyelopoietic Syndromes; Evolution; Fanconi anemia protein; Fanconi' s Anemia; Funding; Genetic; Genomic Instability; Goals; Hematological Disease; Hematopoiesis; Hematopoietic; Hereditary Disease; Hypersensitivity; In Vitro; Inflammation; Inflammatory; Knockout Mice; Knowledge; Lead; Light; Link; Maintenance; Malignant Neoplasms; Modeling; Molecular; Molecular Evolution; Mus; Oxidants; Oxidative Stress; Pancytopenia; Pathogenesis; Pathway interactions; Patients; Physiological; Play; Prevention; Process; Production; Rare Diseases; Reactive Oxygen Species; Research; Research Design; Role; Signal Pathway; Signal Transduction; Staging; System; Testing; Therapeutic; Therapeutic Intervention; Xenograft Model; biological adaptation to stress; cell growth regulation; human disease; in vivo; insight; leukemia; leukemogenesis; mouse model; new therapeutic target; oxidative DNA damage; oxidative damage; progenitor; protein function; public health relevance; repaired; response; stem; transcription factor; tumor progression

DESCRIPTION (provided by applicant): This proposal will investigate the mechanisms by which Fanconi anemia (FA) proteins regulate cellular response to oxidative stress in the context of hematopoiesis. The process of FA disease progression is characterized by bone marrow failure (BMF), clonal proliferation of hematopoietic stem and progenitor (HSC/P) cells, and progression to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). While clinical observations have established a correlation between abnormal accumulation of ROS and FA BMF/leukemic evolution, the molecular pathways in which FA proteins function to modulate physiologic oxidative stress have not been defined. We recently found that FA BM cells accumulated high levels of ROS generated by inflammation and that FA HSC/P cells were extremely sensitive to ROS-induced hematopoietic suppression. We have also shown that abnormal accumulation of ROS played a critical role in the evolution of leukemic clones in FA mouse model. Our most recent identification of the FANCD2- FOXO3a complex and preliminary characterization of impaired anti-oxidant defense in primary BM cells from FA patients open new research opportunities to extend this project to the renewal period. In Aim 1, we will test the hypothesis that physiologic oxidative stress contributes to BMF and progression to clonal hematopoiesis in FA through influencing HSC/P cell proliferation and apoptosis, by assessing the effect of inflammatory ROS on proliferation and apoptosis of HSC/P cells from FA children at three different stages (BMF, MDS, and AML) of disease progression and in a "humanized" NOG/SGM3 mouse xenograft model. In Aim 2, we will test the hypothesis that functional interaction between the FA proteins and other cell signaling pathways play important roles in maintaining normal hematopoiesis under physiologic oxidative stress, with focus on major oxidative stress response pathways involving FOXO3a and cellular anti-oxidant defense systems. In Aim 3, we will test the hypothesis that increased inflammatory ROS and vulnerability of chromosomal DNA to oxidative damage would provide a potential genetic mechanism for FA genomic instability, with focus on the roles of FA proteins in oxidative DNA-damage response and repair, and the functional relationship between inflammatory ROS and genomic instability during FA leukemogenesis using two FA preleukemic models. The knowledge gained from these studies may lead to a new avenue of research designed to further explore the pathogenic role of oxidative stress not only in FA but also in cancer- related hematological diseases in general. In addition, new insights on the potential integration of the FA proteins in other oxidative-stress signaling pathways can suggest new targets for therapeutic prevention and treatment of BMF and cancer progression of these diseases.

描述（由申请人提供）：该提案将研究Fanconi贫血（FA）蛋白在造血中调节细胞对氧化应激的反应的机制。 FA疾病进展的过程的特征是骨髓衰竭（BMF），造血茎和祖细胞（HSC/P）细胞的克隆增殖，以及骨髓增生综合征（MDS）和急性髓样白血病（AML）的进展。尽管临床观察结果已经建立了ROS异常积累与FA BMF/白血病进化之间的相关性，但尚未定义FA蛋白功能调节生理氧化应激的分子途径。我们最近发现，FA BM细胞积累了由炎症产生的高水平ROS，并且FA HSC/P细胞对ROS诱导的造血抑制极为敏感。我们还表明，ROS的异常积累在FA小鼠模型中白血病克隆的演变中起关键作用。我们最近对FASD2-FOXO3A复合物的鉴定以及FA患者原代BM细胞中抗氧化剂防御受损的初步表征开放了将该项目扩展到续签期的新研究机会。在AIM 1中，我们将通过评估炎症ROS对HSC/P细胞的增殖和凋亡的影响，即通过影响HSC/P细胞增殖和凋亡，通过评估炎症性ROS对HSC/P细胞对HSC/P细胞对HSC/P细胞的影响的影响，从而检验以下假设：FA的生理氧化应激和FA中克隆造血的促进。 FA儿童处于疾病进展的三个不同阶段（BMF，MDS和AML）以及“人性化” NOG/SGM3小鼠异种移植模型中。在AIM 2中，我们将测试以下假设：FA蛋白与其他细胞信号通路之间的功能相互作用在生理氧化应激下保持正常造血症中起着重要作用，重点是涉及FOXO3A和细胞抗氧化剂防御系统的主要氧化应激响应途径。在AIM 3中，我们将检验以下假设：炎症性ROS增加以及染色体DNA对氧化损伤的脆弱性将为FA基因组不稳定提供潜在的遗传机制，重点是FA蛋白在氧化DNA受DNA受损反应和修复中的作用，以及使用两个FA Preleukemit模型，在FA白血病发生过程中，炎症性ROS与基因组不稳定性之间的功能关系。从这些研究中获得的知识可能导致一项新的研究途径，旨在进一步探索氧化应激在FA中的致病作用，而且在一般而言是与癌症相关的血液学疾病中。此外，关于FA蛋白在其他氧化压力信号通路中的潜在整合的新见解可以提出用于预防和治疗BMF的新目标，以及这些疾病的癌症进展。