Role of FA proteins in hematopoiesis

FA 蛋白在造血中的作用

基本信息

批准号：
8238120
负责人：
QISHEN PANG
金额：
$ 37.74万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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：
2005-07-05 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8238120
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&apos 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

项目摘要

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. PUBLIC HEALTH RELEVANCE: Oxidative stress has been implicated in the pathogenesis of many human diseases including Fanconi anemia (FA), a blood disease associated with bone marrow failure and cancer. The goal of this project is to define the function of FA proteins in the maintenance of blood cell survival under physiologic oxidative stress. The proposed study will provide valuable information for therapeutic prevention and treatment of bone marrow failure and cancer progression of not only FA but also other blood diseases.

描述（由申请人提供）：该提案将研究范可尼贫血（FA）蛋白在造血过程中调节细胞对氧化应激的反应的机制。 FA疾病进展的过程以骨髓衰竭（BMF）、造血干细胞和祖细胞（HSC/P）克隆增殖以及进展为骨髓增生异常综合征（MDS）和急性髓系白血病（AML）为特征。虽然临床观察已经建立了 ROS 异常积累与 FA BMF/白血病进化之间的相关性，但 FA 蛋白调节生理氧化应激的分子途径尚未确定。我们最近发现FA BM细胞积累了高水平的炎症产生的ROS，并且FA HSC/P细胞对ROS诱导的造血抑制极其敏感。我们还表明，ROS 的异常积累在 FA 小鼠模型中白血病克隆的进化中发挥着关键作用。我们最近对 FANCD2-FOXO3a 复合物的鉴定以及对 FA 患者原代 BM 细胞中受损的抗氧化防御的初步表征，为将该项目延长至更新期开辟了新的研究机会。在目标 1 中，我们将通过评估炎症 ROS 对 HSC/P 细胞增殖和凋亡的影响，检验生理氧化应激通过影响 HSC/P 细胞增殖和凋亡来促进 BMF 和 FA 中克隆造血的进展的假设。 FA 儿童处于疾病进展的三个不同阶段（BMF、MDS 和 AML），并且处于“人源化”NOG/SGM3 小鼠异种移植模型中。在目标 2 中，我们将检验以下假设：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维持正常造血过程中发挥重要作用，重点关注涉及 FOXO3a 和细胞抗氧化防御系统的主要氧化应激反应通路。在目标 3 中，我们将检验以下假设：炎症 ROS 的增加和染色体 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，重点关注 FA 蛋白在氧化 DNA 损伤反应和修复中的作用，以及使用两种 FA 白血病前期模型研究 FA 白血病发生过程中炎症 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会开辟一条新的研究途径，旨在进一步探索氧化应激不仅在 FA 中而且在癌症相关血液疾病中的致病作用。此外，关于 FA 蛋白在其他氧化应激信号通路中的潜在整合的新见解可以为 BMF 和这些疾病的癌症进展的治疗预防和治疗提供新的靶标。公共卫生相关性：氧化应激与许多人类疾病的发病机制有关，包括范可尼贫血 (FA)，这是一种与骨髓衰竭和癌症相关的血液疾病。该项目的目标是确定 FA 蛋白在生理氧化应激下维持血细胞存活的功能。拟议的研究将为 FA 和其他血液疾病的骨髓衰竭和癌症进展的治疗预防和治疗提供有价值的信息。