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 这份K08职业发展奖提案描述了候选人未来5年的培训计划 学术血液学方面的独立内科医生兼科学家，专注于骨髓衰竭综合征。 首席调查员(PI)已在宾夕法尼亚大学获得医学博士和博士学位 (宾夕法尼亚州立大学)，随后在马萨诸塞州综合医院接受内科住院医师培训，奖学金 宾夕法尼亚大学血液学-肿瘤学培训，目前是该大学医学助理教授 宾夕法尼亚州。通过家长K08奖的5年职业发展计划，PI将扩大她的 在造血学、干细胞生物学和免疫学方面的知识和研究技能，以开发 研究获得性再生障碍性贫血(AAA)的克隆性造血的独立研究计划。PI将会是 由造血专家彼得·克莱因博士和咨询委员会指导，后者将促进 少年派的科学和事业发展。 这项拟议中的研究重点是AAA，这是一种威胁生命的血液疾病，影响儿童和成人 通过免疫破坏早期的造血细胞。克隆进化为白血病是一种常见的并发症， 没有有效的预防策略可用。新的数据表明，多达四分之一的AAA患者获得了 体细胞突变，可能有更大的恶变风险。因此，理解克隆人 AAA的造血对于早期发现和改进治疗是很重要的。K08的目标是 AAA的目的是描述AAA的克隆性造血的全谱，并剖析其驱动机制 克隆人的出现。这将通过三个具体目标来实现：1)描述景观和 应用无偏基因分析研究AAA患者骨髓中体细胞突变的发生率 确定对治疗和疾病结果的反应的基因组生物标记物，以及3)表征 候选驱动因素在造血方面的突变。这一项目的成功完成预计将产生 通过提供对临床相关的躯体变化的了解，在现场产生持续和持久的影响 在AAA中，它可以作为新的个性化治疗的遗传生物标记物和靶点。强大的科学性 专业知识和指导委员会的指导和咨询委员会的记录，以及独特的 宾夕法尼亚大学的资源和卓越的研究设施，使这里成为K08奖的理想环境。这 在全面职业发展计划的背景下执行的研究方案将支持PI的 转行成为一名独立的血液学内科医生兼科学家。