Early Clonal Evolution in Acquired Aplastic Anemia

获得性再生障碍性贫血的早期克隆进化

基本信息

批准号：
9089365
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
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9089365
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 Clinical Course of Disease Clonal Evolution Clonal Expansion Complication DNA Data Databases 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 Genomics 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 Outcome Pancytopenia Pathway interactions Patients Pennsylvania Physicians Prevalence Prevention strategy Principal Investigator Production Recurrence Relapse Research Research Personnel Residencies Resources Risk Sampling Scientist Severe Combined Immunodeficiency Signaling Protein Single Nucleotide Polymorphism Skin Somatic Mutation Structure Training Training Programs Transcriptional Regulation Treatment Failure Universities Validation Work actionable mutation base bone marrow failure syndrome career career development cell growth clinically relevant cohort comparative cytokine diabetic exome sequencing genetic analysis genetic makeup genomic biomarker genomic data improved improved outcome in vivo instructor leukemia mutant next generation sequencing oncology patient registry patient subsets personalized approach personalized medicine programs prospective public health relevance rat Piga protein repository research facility response self-renewal skills stem cell biology therapy outcome treatment response

项目摘要

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（由应用程序提供）：该K08职业发展奖提案描述了候选人的5年培训计划，以成为学术血液学的独立身体科学家，重点是骨髓衰竭（BMF）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（宾夕法尼亚大学）的学位，随后在马萨诸塞州综合医院接受内科医学的居民培训，宾夕法尼亚州血液学 - 学研究奖学金培训，并已被任命为2015年7月1日的教练。通过这项5年的职业发展计划，PI将扩大序列的研究和研究序列研究技巧在获得的性性贫血（AAA）中。该提案利用了宾夕法尼亚州/CHOP综合骨髓衰竭中心的大型，通知的AAA患者注册中心。彼得·克莱因（Peter Klein）博士和约翰·马里斯（John Maris）博士，分别是造血和转化基因组研究专家，以及由三位备受推崇的身体科学家组成的咨询委员会，并翻译了研究人员 - 查尔斯·艾布拉姆斯（Charles Abrams）博士，莫妮卡·贝斯勒（Monica Bessler）博士，莫妮卡·贝斯勒（Monica Bessler）和伊丽莎白·赫克斯纳（Elizabeth Hexner）博士将受到PI的科学和职业发展和职业发展和职业发展。拟议的研究重点是AAA，这是一种威胁生命的血液疾病，影响儿童和成人，这是由早期造血细胞免疫抑制引起的。白血病的克隆进化是常见的并发症，没有有效的预防策略。新兴数据表明，多达四分之一的AAA患者获得了体细胞突变，并且可能面临更大的恶性转化风险。因此，了解AAA中的克隆造血作用对于允许早期检测和改善疗法很重要。该提案的目的是表征AAA中克隆造血的全谱，并剖析推动克隆出现的机制。该应用的具体目的是：1）使用公正的遗传分析表征AAA患者骨髓中体细胞突变的景观和流行率，2）确定对治疗和疾病结果反应的基因组生物标志物，以及3）表征甲状腺毒素中候选司机突变的功能。预计该项目的成功完成将通过对AAA中临床上相关的躯体变化的了解，从而在该领域产生持续和持久的影响，该疗法可以用作新的个性化疗法的遗传生物标志物和靶标。 PI的导师和咨询委员会的强大科学专业知识以及Mentalship Track Record，以及宾夕法尼亚州的独特资源和出色的研究设施，这是该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执行，将支持PI的职业过渡，成为血液学独立的身体科学家。