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标

• 批准号: 8680357
• 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/8680357
• 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.

描述(由申请人提供)：建议的K08职业发展奖申请描述了一项为期5年的计划，以支持首席研究员Kim-Hien Dao博士，他是一名临床科学家，正处于俄勒冈健康与科学大学(OHSU)发展独立研究计划的过渡阶段。道博士的研究经历始于她在人类纤维肉瘤细胞系的癌症生物学和RAS信号领域的博士培训。在完成内科住院医师培训后，她在加州大学圣地亚哥分校完成了血液学-肿瘤学的奖学金培训。通过这段经历，作为加州再生医学研究所项目的临床研究员，她在Catriona Jamieson博士的指导下获得了为期2年的博士后研究经验，并被介绍到造血干细胞生物学。目前的申请概述了在Grover Bagby博士和Brian Druker博士的指导下，通过正式的职业发展计划进行的额外多年的指导性研究。道博士将利用由国立卫生研究院资助的OHSU非常成功的医学科学家组成的顾问委员会，以及在范可尼贫血(FA)研究、干细胞生物学、癌细胞生物学和酪氨酸激酶信号转导方面拥有国际公认专业知识的研究环境。拟议的研究将集中于调查为什么FA途径基因的功能突变，经典地被描述为DNA损伤反应途径，导致造血干细胞在干细胞适合性方面存在固有缺陷。总体假设是，FA核心复合体参与稳定β-连环蛋白的核功能，并破坏这种功能 相互作用是FA缺乏的造血干细胞有限复制和存活的分子基础。主要目的是从机制上确定FA通路和Wnt/β-catenin信号之间的相互作用。具体目标包括：1)确定FA核心复合体的蛋白质是否增加蛋白质稳定性和/或β-连环素的核定位；2)确定FANCL是否直接使单泛素化的β-连环素导致其核活性增强；以及3)在FA体内模型中确定FA缺陷的造血干细胞在发育和骨髓衰竭过程中Wnt/β-连环素信号的特定扰动。如果造血干细胞对恶性克隆进化的易感性被定义为Wnt/β-catenin信号的缺陷，那么，通过操纵Wnt/β-catenin途径的靶点，可以在选择性微环境中恢复造血干细胞的适合性，可能会颠覆骨髓衰竭患者的疾病进展。K08导师奖将通过保护她在研究项目和职业发展计划上的努力，直接推动她的科学发展。这些过渡步骤对于她实现长期职业目标是必要的，她的目标是成为一名拥有持续的外部资金的多产的、独立的学术医学研究人员。