Early Clonal Evolution in Acquired Aplastic Anemia

获得性再生障碍性贫血的早期克隆进化

• 批准号: 10393146
• 负责人: Daria Babushok
• 金额: $ 8.88万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2022-03-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393146
• 关键词: Adult; Advisory Committees; Affect; Aplastic Anemia; Automobile Driving; Award; Blood Cells; Bone Marrow; Career Mobility; Cells; Child; Clonal Evolution; Complication; Data; Development Plans; Disease Marker; Disease Outcome; Doctor of Medicine; Doctor of Philosophy; Early Diagnosis; Environment; Fellowship; Fostering; Fright; General Hospitals; Genetic Markers; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Immune mediated destruction; Immunology; Internal Medicine; K-Series Research Career Programs; Knowledge; Life; Malignant - descriptor; Massachusetts; Medicine; Mentors; Mentorship; Mutation; Oncology; Parents; Patients; Pennsylvania; Physicians; Prevalence; Prevention strategy; Principal Investigator; Relapse; Research; Residencies; Resources; Risk; Scientist; Somatic Mutation; Training; Training Programs; Treatment Failure; Universities; bone marrow failure syndrome; career development; clinically relevant; driver mutation; genetic analysis; genomic biomarker; improved; leukemia; personalized medicine; professor; programs; research facility; response; response biomarker; skills; stem cell biology; therapy outcome

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.

项目摘要/摘要 该K08职业发展奖提案描述了候选人的5年培训计划，以成为 一个独立的学术血液学身体主义者，重点是骨髓衰竭综合征。 首席研究员（PI）已完成医学博士学位和博士学位。宾夕法尼亚大学的学位 （宾夕法尼亚 宾夕法尼亚州血液学 - 肿瘤培训，目前是大学医学助理教授 宾夕法尼亚州。通过父母K08奖的5年职业发展计划，PI将扩大她 造血，干细胞生物学和免疫学的知识和研究技能，以开发 在获得性障碍性贫血（AAA）中研究克隆造血的独立研究计划。 PI将是 由造血专家彼得·克莱因（Peter Klein）和咨询委员会的指导 PI的科学和职业发展。 拟议的研究重点是AAA，这是一种影响儿童和成人的血液疾病 通过免疫破坏早期造血细胞。白血病的克隆进化是一种常见的并发症，有 没有有效的预防策略。新兴数据表明多达四分之一的AAA患者获得 体细胞突变，可能面临更大的恶性转化风险。因此，了解克隆 AAA中的造血对允许早期检测和改善疗法很重要。 K08的目标 奖项是为了表征AAA中克隆造血的全谱，并剖析驾驶的机制 克隆的出现。这将以三个特定的目的来完成：1）特征是景观和 使用公正的遗传分析，AAA患者骨髓中体细胞突变的患病率为2） 确定对治疗和疾病结果反应的基因组生物标志物，3）表征 造血中的候选驾驶员突变。预计该项目的成功完成将有一个 通过提供对临床相关的体细胞改变的理解，对现场的持续和持久影响 在AAA中，可以用作新的个性化疗法的遗传生物标志物和靶标。强大的科学 PI的导师和咨询委员会的专业知识以及Mentalship的记录，以及独特的 宾夕法尼亚州的资源和出色的研究设施，使这是该K08奖的理想环境。这 在全面的职业发展计划的背景下执行的研究计划将支持PI的 职业过渡成为血液学独立的身体科学家。