Early Clonal Evolution in Acquired Aplastic Anemia

项目总结/摘要 本K 08职业发展奖提案描述了候选人的5年培训计划， 一个独立的医生，科学家在学术血液学，重点是骨髓衰竭综合征。 主要研究者（PI）已完成医学博士学位。和博士宾夕法尼亚大学的学位 （宾夕法尼亚大学），随后在马萨诸塞州总医院接受内科住院医师培训， 在宾夕法尼亚大学接受血液肿瘤学培训，目前是该校医学助理教授 宾夕法尼亚州。通过母公司K 08奖的5年职业发展计划，PI将扩大她的 造血，干细胞生物学和免疫学的知识和研究技能，以发展一个 研究获得性再生障碍性贫血（aAA）中克隆造血的独立研究项目。PI将 由造血专家Peter Klein博士以及咨询委员会指导， 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， 通过免疫破坏早期造血细胞克隆性演变为白血病是一种常见的并发症， 没有有效的预防战略。新的数据表明，多达四分之一的aAA患者获得 体细胞突变，并可能在恶性转化的风险更大。因此，了解克隆 aAA中的造血对于允许早期检测和改进的治疗是重要的。K 08的目标 该奖项旨在描述aAA中克隆造血的全谱特征，并剖析驱动aAA的机制。 克隆人的出现这将通过三个具体目标来实现：1）描述景观， 使用无偏遗传分析的aAA患者骨髓中体细胞突变的患病率，2） 鉴定对治疗和疾病结果的反应的基因组生物标志物，以及3）表征 造血中的候选驱动突变。该项目的顺利完成，预计将有一个 通过提供对临床相关躯体改变的理解，在该领域产生持续和持久的影响 在aAA中，它可以作为遗传生物标志物和新的个性化治疗的靶点。强大的科学 专业知识和指导的PI的导师和咨询委员会的跟踪记录，连同独特的 资源和宾夕法尼亚大学优秀的研究设施，使这一K 08奖的理想环境。这 在全面职业发展计划的背景下进行的研究计划将支持PI的 职业转型成为血液学的独立医生科学家。

PROJECT SUMMARY/ABSTRACT 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 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 is currently an Assistant Professor in Medicine at the University of Pennsylvania. Through the 5-year career development plan of the parent K08 award, the PI will expand her knowledge and research skills in hematopoiesis, stem cell biology, and immunology in order to develop an independent research program studying clonal hematopoiesis in acquired aplastic anemia (aAA). The PI will be mentored by Dr. Peter Klein, an expert on hematopoiesis, as well as the Advisory Committee, who will foster 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 the K08 award is to characterize the full spectrum of clonal hematopoiesis in aAA and to dissect the mechanisms driving emergence of clones. This will be accomplished in three specific aims: 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.