Beta-catenin is a molecular target of the Fanconi anemia core complex

β-连环蛋白是范可尼贫血核心复合物的分子靶点

• 批准号: 8224213
• 负责人: Kim-Hien T Dao
• 金额: $ 12.83万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8224213
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Advisory Committees; Animals; Area; Automobile Driving; Award; Binding; Biological; Biological Assay; Blood; California; Cancer Biology; Cell Death; Cell Line; Cells; Cellular biology; Clinical; Clonal Evolution; Complement; Complex; Confocal Microscopy; Cycloheximide; DNA Damage; Data; Defect; Development; Development Plans; Disease; Disease Progression; Disease model; Doctor of Philosophy; Environment; Extramural Activities; Fanconi anemia protein; Fanconi' s Anemia; Fellowship; Funding; Genes; Genetic; Goals; Health Sciences; Hematology; Hematopoietic stem cells; Human; Individual; Inferior; Inherited; Institutes; Internal Medicine; K-Series Research Career Programs; Longevity; Maintenance; Malignant - descriptor; Medical; Medicine; Mentors; Molecular; Molecular Target; Mono-S; Natural Selections; Nuclear; Nuclear Extract; Oregon; Outcome; Pancytopenia; Pathway interactions; Patients; Phase; Post-Translational Protein Processing; Predisposition; Principal Investigator; Process; Property; Protein Tyrosine Kinase; Proteins; Regenerative Medicine; Reporter; Research; Research Personnel; Research Project Grants; Residencies; Role; Scientific Advances and Accomplishments; Scientist; Signal Transduction; Stem Cell Development; Stem cells; Testing; Training; Transgenic Organisms; Tumor Necrosis Factor-alpha; Ubiquitination; United States National Institutes of Health; Universities; Western Blotting; base; beta catenin; cancer cell; career; career development; experience; fitness; improved functioning; in vivo Model; loss of function mutation; mouse model; mutant; oncology; outcome forecast; overexpression; prevent; programs; protein complex; response; sarcoma; stem cell biology; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): The proposed K08 career development award application describes a 5-year program for the support of the principal investigator, Dr. Kim-Hien Dao, who is a clinician scientist in the transitional phases of developing an independent research program at Oregon Health & Science University (OHSU). Dr. Dao's research experience began with her PhD training in the area of cancer biology and RAS signaling in human fibro sarcoma cell lines. After Internal Medicine residency training, she completed fellowship training in Hematology-Oncology at the University of California at San Diego. Through this experience, as a Clinical Fellow Scholar in the California Institute for Regenerative Medicine Program, she acquired a 2-year postdoctoral research experience under the direction of Dr. Catriona Jamieson and was introduced to hematopoietic stem cell biology. The current application outlines additional years of mentored research with a formal career development plan under the guidance of Drs. Grover Bagby and Brian Druker. Dr. Dao will take advantage of an advisory committee composed of highly successful, NIH-funded medical scientists at OHSU and a research environment with internationally-recognized expertise in Fanconi Anemia (FA) research, stem cell biology, cancer cell biology, and tyrosine kinase signaling. The research proposed will focus on investigating why loss of function mutations in genes of the FA pathway, classically described as a DNA damage response pathway, give rise to hematopoietic stem cells with inherent defects in stem cell fitness. The overall hypothesis is that the FA core complex is involved in stabilizing the nuclear function of beta-catenin and the disruption of this interaction is the molecular basis for the limited replicative and survival potential of FA deficiet hematopoietic stem cells. The main objective is to mechanistically define the interaction between FA pathway and Wnt/beta-catenin signaling. The specific aims include: 1) Determine whether proteins of the FA core complex increase protein stability and/or nuclear localization of beta-catenin; 2) Determine whether FANCL directly mono-ubiquitinates beta-catenin leading to its enhanced nuclear activity; and 3) Define specific perturbations in Wnt/beta-catenin signaling in FA-deficient hematopoietic stem cells during development and bone marrow failure in an in vivo model of FA. If the susceptible pool of hematopoietic stem cells to malignant clonal evolution is defined by deficient Wnt/beta-catenin signaling, then disease progression in patients with bone marrow failure might be subverted by manipulating targets of the Wnt/beta-catenin pathway that would restore the fitness of the hematopoietic stem cells in a selective microenvironment. The mentored K08 award will directly advance her scientific development by protecting her effort towards her research project and career development plan. These transitional steps are necessary for her to achieve her long-term career goal of becoming a productive, independent researcher in academic medicine with sustained extramural funding. PUBLIC HEALTH RELEVANCE: The project proposed will investigate why the blood stem cells from patients who inherit a loss-of-function mutation in one of the genes of the Fanconi anemia pathway are highly susceptible to cell death yet also highly susceptible to conversion into an acute leukemia. We will define the mechanisms driving this process in relation to abnormal Wnt/beta-catenin signaling, a pathway that normally controls the quantity and quality of blood stem cells during the lifespan of an individual. We may discover markers that predict prognosis or identify Wnt/beta-catenin pathway targets that may be manipulated to improve the function of blood stem cells in Fanconi anemia disease and acquired bone marrow failure, and therefore, prevent conversion into an acute leukemia.

描述（由申请人提供）：拟议的K 08职业发展奖申请描述了一个为期5年的计划，以支持主要研究者Kim Hien Dao博士，他是俄勒冈州健康与科学大学（OHSU）发展独立研究计划过渡阶段的临床科学家。Dao博士的研究经历始于她在癌症生物学和人类乳腺癌细胞系中RAS信号传导领域的博士培训。在完成内科住院医师培训后，她在圣地亚哥的加州大学完成了血液肿瘤学的奖学金培训。通过这段经历，作为加州再生医学项目研究所的临床研究员学者，她在Catriona Jamieson博士的指导下获得了2年的博士后研究经验，并被介绍给造血干细胞生物学。目前的应用程序概述了额外几年的指导研究与正式的职业发展计划的指导下博士格罗弗巴格比和布赖恩德鲁克。Dao博士将利用由OHSU非常成功的NIH资助的医学科学家组成的咨询委员会以及在Fanconi贫血（FA）研究，干细胞生物学，癌细胞生物学和酪氨酸激酶信号传导方面具有国际公认的专业知识的研究环境。拟议的研究将集中于调查为什么FA途径基因中的功能突变丧失，经典地描述为DNA损伤反应途径，产生具有干细胞适应性固有缺陷的造血干细胞。总的假设是FA核心复合物参与稳定β-连环蛋白的核功能，并破坏这种功能。 这种相互作用是FA缺陷造血干细胞有限的复制和存活潜力的分子基础。主要目的是机械地定义FA通路和Wnt/β-连环蛋白信号传导之间的相互作用。具体目标包括：1）确定FA核心复合物的蛋白质是否增加β-连环蛋白的蛋白质稳定性和/或核定位; 2）确定FANCL是否直接单泛素化β-连环蛋白，导致其增强的核活性;和3）在FA的体内模型中，在发育和骨髓衰竭期间，确定FA缺陷型造血干细胞中Wnt/β-连环蛋白信号传导的特异性扰动。如果造血干细胞对恶性克隆进化的易感库是由Wnt/β-连环蛋白信号传导缺陷定义的，那么骨髓衰竭患者的疾病进展可能会通过操纵Wnt/β-连环蛋白途径的靶点来逆转，这将恢复造血干细胞的适应性。在选择性微环境中的干细胞。指导K 08奖将直接促进她的科学发展，保护她对她的研究项目和职业发展计划的努力。这些过渡步骤是必要的，她实现她的长期职业目标，成为一个富有成效的，独立的研究人员在学术医学与持续的校外资金。 公共卫生相关性：该项目将研究为什么来自Fanconi贫血途径基因之一的功能缺失突变患者的血液干细胞极易发生细胞死亡，但也极易转化为急性白血病。我们将定义驱动这一过程的机制与异常Wnt/β-连环蛋白信号传导有关，这是一种在个体生命周期中通常控制造血干细胞数量和质量的途径。我们可能会发现预测预后的标志物或识别Wnt/β-连环蛋白通路靶点，这些靶点可以被操纵以改善范可尼贫血病和获得性骨髓衰竭中造血干细胞的功能，从而防止转化为急性白血病。