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K08职业发展奖申请描述了一项为期5年的支持计划，以支持主要研究者Kim-Hien Dao博士，他是俄勒冈健康与科学大学（OHSU）开发独立研究计划的过渡阶段的临床医生。 Dao博士的研究经验始于她在人体纤维肉瘤细胞系中癌症生物学和RAS信号传导领域的博士学位培训。在内科医学训练后，她在加利福尼亚大学圣地亚哥大学完成了血液肿瘤学奖学金培训。通过这一经验，作为加利福尼亚再生医学研究所的临床学者，她在Catriona Jamieson博士的指导下获得了一项为期2年的博士后研究经验，并被引入造血干细胞生物学。当前的应用程序在DRS的指导下，通过正式的职业发展计划概述了多年的指导研究。格罗弗·巴比（Grover Bagby）和布莱恩·德鲁克（Brian Druker）。 DAO博士将利用由OHSU的高度成功，由NIH资助的医学科学家组成的咨询委员会，以及具有国际知名度为Fanconi贫血研究（FA）研究，干细胞生物学，癌细胞生物学和酪氨酸激酶信号的研究环境。提出的研究将集中于研究为什么FA途径基因中功能突变的丧失（通常被描述为DNA损伤反应途径）会导致造血干细胞具有干细胞适应性固有缺陷的造血干细胞。总体假设是，FA核心复合物参与稳定β-catenin的核功能和此破坏 相互作用是FA缺乏型造血干细胞的有限复制和生存潜力的分子基础。主要目的是机械地定义FA途径与Wnt/beta-catenin信号传导之间的相互作用。具体目的包括：1）确定FA核复合物的蛋白是否会增加β-catenin的蛋白质稳定性和/或核定位置； 2）确定FANCL是否直接单次泛素化β-catenin导致其核活性增强； 3）在FA的发育过程中，在FA缺陷型造血干细胞中定义了Wnt/β-catenin信号传导的特定扰动，而在FA的体内模型中，定义了骨髓衰竭。如果造血干细胞对恶性克隆进化的易感库是由Wnt/β-catenin信号传导定义的，那么骨髓衰竭患者的疾病进展可能会因操纵Wnt/β-catenin途径的靶标而被颠覆，从而恢复了尚未恢复肢发型干细胞的适应性。指导的K08奖将通过保护她在研究项目和职业发展计划上的努力来直接推动其科学发展。这些过渡步骤对于她实现了她的长期职业目标是必要的，即成为一名具有持续校外资金的学术医学的独立独立研究人员。 公共卫生相关性：拟议的项目将研究为什么在Fanconi贫血途径的一个基因中继承了功能丧失突变的患者的血液干细胞非常容易受到细胞死亡的影响，又非常容易转化为急性白血病。我们将定义与异常的Wnt/beta-catenin信号传导有关的机制，该途径通常控制一个个体的寿命中血管细胞的数量和质量。我们可能会发现预测预后或鉴定Wnt/β-catenin途径靶标的标记物，这些靶标可能会被操纵以改善Fanconi贫血疾病中血管细胞的功能并获得骨髓衰竭，从而防止转化为急性白血病。