Early Clonal Evolution in Acquired Aplastic Anemia

 描述（由申请人提供）：此K 08职业发展奖提案描述了候选人的5年培训计划，成为学术血液学的独立医生-科学家，重点是骨髓衰竭（BMF）综合征。主要研究者（PI）已完成医学博士学位。和博士在宾夕法尼亚大学（Penn）获得学位，随后在马萨诸塞州总医院接受内科住院医师培训，在Penn接受血液肿瘤学研究金培训，并于2015年7月1日起被任命为讲师。通过这个5年职业发展计划，PI将扩大她在造血和干细胞生物学方面的知识和研究技能，以开发一个独立的研究项目，研究获得性再生障碍性贫血（aAA）的克隆造血。该提案利用了Penn/CHOP综合骨髓衰竭中心大量注释良好的aAA患者登记。共同导师Peter Klein博士和John Maris博士，分别是造血和转化基因组研究方面的专家，以及由三位备受推崇的医生-科学家和转化研究人员组成的咨询委员会-Charles Abrams博士，Monica Bessler博士和Elizabeth Hexner博士将指导PI的科学和职业发展。拟议的研究重点是aAA，这是一种危及生命的血液疾病，影响儿童和成人，由早期造血细胞的免疫破坏引起。克隆性白血病是一种常见的并发症，目前尚无有效的预防策略。新出现的数据表明，多达四分之一的aAA患者获得体细胞突变，并可能处于更大的恶性转化风险。因此，了解aAA中的克隆造血对于允许早期检测和改进治疗是重要的。该提案的目的是表征aAA中克隆造血的全谱，并剖析驱动克隆出现的机制。本申请的具体目的是：1）使用无偏遗传分析表征aAA患者骨髓中体细胞突变的景观和患病率，2）鉴定对治疗和疾病结果的反应的基因组生物标志物，和3）表征造血中候选驱动突变的功能。该项目的成功完成预计将对该领域产生持续和持久的影响，通过提供对aAA中临床相关体细胞改变的理解，这可以作为新的个性化治疗的遗传生物标志物和靶点。PI导师和咨询委员会强大的科学专业知识和指导记录，以及宾夕法尼亚大学独特的资源和优秀的研究设施，使其成为K 08奖的理想环境。这项研究计划，在一个全面的职业发展计划的背景下进行，将支持PI的职业过渡，成为一个独立的医生，科学家在血液学。

 DESCRIPTION (provided by applicant): This K08 Career Development Award proposal describes the candidate's 5-year training program to become an independent physician-scientist in academic Hematology, with a focus on bone marrow failure (BMF) syndromes. The Principal Investigator (PI) has completed M.D. and Ph.D. Degrees at the University of Pennsylvania (Penn), followed by residency training in Internal Medicine at the Massachusetts General Hospital, fellowship training in Hematology-Oncology at Penn, and has been appointed an Instructor starting July 1, 2015. Through this 5-year career development plan, the PI will expand her knowledge and research skills in hematopoiesis and stem cell biology in order to develop an independent research program studying clonal hematopoiesis in acquired aplastic anemia (aAA). This proposal takes advantage of a large, well-annotated aAA patient registry at the Penn/CHOP Comprehensive Bone Marrow Failure Center. Co-Mentors Dr. Peter Klein and Dr. John Maris, experts on hematopoiesis and translational genomic research, respectively, as well as the Advisory Committee composed of three highly regarded physician-scientists and translational researchers- Dr. Charles Abrams, Dr. Monica Bessler, and Dr. Elizabeth Hexner will mentor the PI's scientific and career development. The proposed research focuses on aAA, a life-threatening blood disease, affecting children and adults, caused by immune destruction of early hematopoietic cells. Clonal evolution to leukemia is a common complication, with no effective prevention strategy available. Emerging data indicate that up to a quarter of aAA patients acquire somatic mutations, and may be at a greater risk of malignant transformation. Therefore, understanding clonal hematopoiesis in aAA is important to allow for early detection and improved therapies. The objective of this proposal is to characterize the full spectrum of clonal hematopoiesis in aAA and to dissect the mechanisms driving emergence of clones. Specific Aims of this application are: 1) Characterize the landscape and prevalence of somatic mutations in the bone marrow of aAA patients using an unbiased genetic analysis, 2) Identify genomic biomarkers of response to therapy and disease outcomes, and 3) Characterize the function of candidate driver mutations in hematopoiesis. The successful completion of this project is expected to have a sustained and lasting impact in the field by providing an understanding of clinically-relevant somatic alterations in aAA, which could serve as genetic biomarkers and targets for new personalized therapies. The strong scientific expertise and the mentorship track-record of the PI's Mentor and Advisory Committee, together with the unique resources and outstanding research facilities at Penn make this an ideal environment for this K08 Award. This research program, performed in the context of a comprehensive career development plan, will support the PI's career transition to become an independent physician-scientist in Hematology.