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

描述（由申请人提供）：拟议的K08职业发展奖申请描述了一个为期5年的计划，以支持首席研究员Kim-Hien Dao博士，他是俄勒冈健康与科学大学（OHSU）发展独立研究计划的过渡阶段的临床科学家。Dao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的临床研究员，她在Catriona Jamieson博士的指导下获得了2年的博士后研究经验，并介绍了造血干细胞生物学。目前的申请概述了在博士的指导下，额外几年的指导研究和正式的职业发展计划。格罗弗·巴格比和布莱恩·德鲁克。Dao博士将利用OHSU由非常成功的美国国立卫生研究院资助的医学科学家组成的咨询委员会，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传导方面具有国际公认专业知识的研究环境。这项研究将集中于研究为什么FA通路基因的功能突变缺失会导致造血干细胞在干细胞适应性方面存在固有缺陷。FA通路通常被描述为DNA损伤反应通路。总的假设是FA核心复合物参与了-连环蛋白核功能的稳定和破坏

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.