Functional evaluation of clonal hematopoiesis of indeterminate potential (CHIP)

不确定潜能克隆造血功能（CHIP）的功能评估

• 批准号: 10399974
• 负责人: Juan M. Barajas
• 金额: $ 6.47万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399974
• 关键词: 21 year old; Acute Myelocytic Leukemia; Adult; Affect; Age; Aging; Allogenic; Animal Model; Bar Codes; Behavior; Biological Models; Biometry; Blood; Blood Cells; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Cell Compartmentation; Cells; Chemotherapy and/or radiation; Childhood; Chronic; Clinical; Clonal Expansion; Clonal Hematopoietic Stem Cell; Clonality; Cohort Studies; Computational Biology; Core Facility; DNMT3a; Data; Detection; Development; Donor person; Dysmyelopoietic Syndromes; Educational process of instructing; Educational workshop; Elderly; Environment; Epigenetic Process; Evaluation; Fellowship; Flow Cytometry; Foundations; Functional disorder; General Population; Genes; Genomics; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Heritability; In Vitro; Incidence; Individual; Inflammation; Ischemic Stroke; JAK2 gene; Knock-in; Label; Laboratories; Lead; Learning; Malignant Childhood Neoplasm; Mentors; Modeling; Molecular; Molecular Biology; Monitor; Mus; Mutant Strains Mice; Mutation; Myeloproliferative disease; Outcome; Patients; Pediatric cohort; Postdoctoral Fellow; Proto-Oncogene Protein c-kit; Radiation exposure; Relapse; Research Personnel; Resource Development; Resources; Risk; Saint Jude Children' s Research Hospital; Sampling; Second Primary Cancers; Somatic Mutation; Stress; TP53 gene; Testing; Therapeutic; Time; Training; Transplant Recipients; Transplantation; Work; adverse outcome; cardiovascular disorder risk; career development; cell type; cohort; conditional knockout; congenic; deep sequencing; experience; experimental study; follow-up; functional genomics; gene function; genetic analysis; genome sequencing; hematopoietic stem cell expansion; high risk; in vivo; leukemia; malignant state; mouse model; next generation sequencing; normal aging; novel therapeutic intervention; patient population; pediatric patients; prevent; response; screening; stem cell biology; stressor; transplantation therapy

ABSTRACT Clonal hematopoiesis of indeterminate potential (CHIP) is the expansion of hematopoietic stem cell (HSC) clones with acquired mutations thought to be caused by normal aging or bone marrow stress. People with CHIP clones are at increased risk of developing a blood cancer, cardiovascular disease or ischemic stroke. Our understanding of the pathophysiology of CHIP progression has been limited to large next generation sequencing studies performed in adults. Therefore, the molecular mechanisms and clonal expansion and dynamics in the context of CHIP mutations, are poorly understood. As a postdoctoral fellow in the Obeng laboratory and co-sponsored by Dr. Mitch Weiss, I will study the pathobiological mechanisms of CHIP expansion in pediatric patients and using mouse models. In Aim 1, I will use targeted genomic sequencing to define the incidence and clinical complications of CHIP in a large, well-annotated cohort of pediatric patients. In this aim, I will help define CHIP incidence in poorly studied cohort and expand on my training in computational biology and functional genomics. In Aim 2, I will use molecular barcoding to label and track the clonal dynamics of hematopoietic stem cells (HSCs) expressing different, common CHIP mutations. I will determine how different mutations affect clonal expansion in different HSC compartments and how chronic inflammation and aging affect the behavior of different CHIP clones. In this aim, I will help define how HSC clones harboring CHIP-related mutations expand in vivo. Collectively, these aims draw upon my prior molecular and computational biology experience and provide new training in stem cell biology and functional genomics. The technical and intellectual resources at St. Jude Children's Research Hospital provide the optimal environment for my training. In addition to the exceptional training and access to the state-of-the-art core facilities available at St. Jude, I will also take advantage of numerous career development resources during my fellowship in the form of institutional and outside workshops, networking opportunities, teaching and mentoring opportunities, and seminars. I will have access to a large, well-annotated clinical cohort, well-characterized animal models, and state-of-the-art genome sequencing and flow cytometry facilities. I will work closely with our collaborators in Computational Biology and Biostatistics to learn how to analyze the data generated by my experiments. I will work with experienced, dedicated mentors and will have access to career development opportunities that will help me become an independent investigator. My studies will help define the molecular features that allow CHIP clones to persist and expand in vivo. A better understanding of the pathobiology of CHIP clones will help guide how CHIP progression is monitored and inform therapeutic considerations in patients of all ages.

抽象的 不确定电势（CHIP）的克隆造血是造血干细胞（HSC）克隆的膨胀 被认为是由正常衰老或骨髓胁迫引起的，被发现的突变。有芯片克隆的人 患有血液癌，心血管疾病或缺血性中风的风险增加。我们的理解 芯片进展的病理生理学局限于大型下一代测序研究 在成年人中进行。因此，在 芯片突变，知之甚少。作为Obeng实验室的博士后研究员，并共同赞助 米奇·魏斯（Mitch Weiss）博士，我将研究儿科患者芯片扩张的病理生物学机制并使用 鼠标模型。在AIM 1中，我将使用靶向基因组测序来定义发病率和临床 小儿患者的大型，通知的大量同类群体中的芯片并发症。在此目标中，我将帮助定义芯片 研究较少的队列的发病率并扩展了我在计算生物学和功能基因组学方面的培训。 在AIM 2中，我将使用分子条形码标记和跟踪造血干细胞的克隆动力学 （HSC）表达不同的常见芯片突变。我将确定不同的突变如何影响克隆 不同HSC室的扩展以及慢性炎症和衰老如何影响 不同的芯片克隆。在此目标中，我将帮助定义HSC克隆如何携带与芯片有关的突变的扩展 体内。总的来说，这些目标借鉴了我先前的分子和计算生物学经验，并提供 干细胞生物学和功能基因组学的新培训。圣裘德的技术和智力资源 儿童研究医院为我的培训提供了最佳的环境。除了出色 我还将利用培训和进入最先进的核心设施，我还将利用 我以机构和外部研讨会形式的团契期间的许多职业发展资源， 网络机会，教学机会和研讨会。我将可以访问一个大的 被宣布良好的临床队列，特征良好的动物模型以及最先进的基因组测序和 流式细胞仪设施。我将与我们的计算生物学和生物统计学合作者紧密合作，以 了解如何分析我的实验生成的数据。我将与经验丰富，敬业的导师合作 并将获得职业发展机会，这将帮助我成为一名独立的调查员。 我的研究将有助于定义允许芯片克隆在体内持续和扩展的分子特征。更好 了解芯片克隆的病理生物学将有助于指导如何监控芯片进展并告知芯片的进展 所有年龄段患者的治疗考虑因素。