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: 9923728
• 负责人: Daria Babushok
• 金额: $ 16.98万
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923728
• 关键词: Acute Erythroblastic Leukemia; Acute Myelocytic Leukemia; Address; Adolescent and Young Adult; Adult; Advisory Committees; Affect; Alleles; Aplastic Anemia; Automobile Driving; Award; Biological Assay; Blood; Blood Cells; Bone Marrow; CD34 gene; Career Mobility; Cell Line; Cell Survival; Cells; Characteristics; Child; Childhood; Clinical; Clonal Evolution; Clonal Expansion; Complication; DNA; Data; Development Plans; Diagnosis; Disease; Disease Marker; Disease Outcome; Doctor of Medicine; Doctor of Philosophy; Dysmyelopoietic Syndromes; Early Diagnosis; Environment; Fellowship; Fright; General Hospitals; Genes; Genetic; Genetic Markers; Genotype; Goals; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; High Prevalence; Human; Immune; Immunity; Internal Medicine; K-Series Research Career Programs; Knowledge; Lead; Life; Malignant - descriptor; Massachusetts; Measures; Mentors; Mentorship; Mus; Mutate; Mutation; Myeloproliferative disease; Non obese; Oncology; Outcome; Pancytopenia; Pathway interactions; Patients; Pennsylvania; Physicians; Prevalence; Prevention strategy; Principal Investigator; Production; Recurrence; Relapse; Research; Residencies; Resources; Risk; SNP array; Sampling; Scientist; Severe Combined Immunodeficiency; Signaling Protein; Skin; Somatic Mutation; Structure; Therapeutic; Training; Training Programs; Transcriptional Regulation; Treatment Failure; Universities; Validation; base; bone marrow failure syndrome; career; career development; cell growth; clinically relevant; cohort; comparative; cytokine; diabetic; driver mutation; exome sequencing; genetic analysis; genetic makeup; genomic biomarker; genomic data; improved; improved outcome; in vivo; instructor; leukemia; mutant; next generation sequencing; patient registry; patient subsets; personalized approach; personalized medicine; programs; prospective; public health relevance; rat Piga protein; repository; research facility; response; response biomarker; self-renewal; skills; stem cell biology; therapy outcome; translational genomics; translational scientist; treatment response

 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.

 描述（由申请人提供）：这份 K08 职业发展奖提案描述了候选人的 5 年培训计划，旨在成为学术血液学领域的独立医师科学家，重点关注骨髓衰竭 (BMF) 综合征。首席研究员（PI）已完成医学博士和博士学位。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，在宾夕法尼亚大学进行血液肿瘤学进修培训，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 将扩展她在造血和干细胞生物学方面的知识和研究技能，以便开发一个研究克隆造血的独立研究项目 获得性再生障碍性贫血（aAA）。该提案利用了 Penn/CHOP 综合骨髓衰竭中心的大型、注释清楚的 aAA 患者登记处。联合导师 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，以及由三位备受尊敬的医学科学家和转化研究人员 Charles Abrams 博士、Monica Bessler 博士和 Elizabeth Hexner 博士组成的咨询委员会将指导 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。克隆进化为白血病是一种常见的并发症，目前尚无有效的预防策略。新数据表明，多达四分之一的 aAA 患者发生体细胞突变，并且可能面临更大的恶变风险。因此，了解 aAA 中的克隆造血作用对于早期检测和改进治疗非常重要。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。该应用的具体目标是：1) 使用无偏见的遗传分析来表征 aAA 患者骨髓中体细胞突变的情况和患病率，2) 识别对治疗和疾病结果反应的基因组生物标志物，以及 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通过提供对 aAA 中临床相关体细胞改变的了解，对该领域产生持续和持久的影响，这可以作为新的个性化疗法的遗传生物标志物和目标。 PI 导师和咨询委员会强大的科学专业知识和指导记录，加上宾夕法尼亚大学独特的资源和出色的研究设施，使这里成为 K08 奖的理想环境。该研究计划在全面的职业发展计划的背景下进行，将支持 PI 的职业转型，成为血液学领域的独立医师科学家。