Towards Precision Medicine in Childhood Acquired Aplastic Anemia

儿童获得性再生障碍性贫血的精准医学

• 批准号: 8770478
• 负责人: JACLYN A BIEGEL
• 金额: $ 56万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8770478
• 关键词: Address; Adult; Anemia; Aplastic Anemia; Architecture; Area; Bioethics; Biology; Blood; Blood Cells; Bone Marrow; Bone Marrow Cells; Candidate Disease Gene; Caring; Cells; Characteristics; Child; Childhood; Clinic; Clinical; Clinical Management; Clinical Medicine; Clonal Evolution; Clustered Regularly Interspaced Short Palindromic Repeats; Comparative Genomic Analysis; Constitutional; DNA; DNA Library; DNA Resequencing; Development; Diagnosis; Disease; Disease remission; Dysmyelopoietic Syndromes; Event; Evolution; Exhibits; Exposure to; Fibroblasts; Functional disorder; Gene Mutation; Genes; Genetic; Genomics; Growth; Health; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemorrhage; Immune; In Vitro; Individual; Infection; Inflammatory; Inherited; Institutional Review Boards; Investigation; Lead; Life; Maps; Mediating; Medical; Medicine; Monoclonal Antibody R24; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Outcome; Pancytopenia; Pathogenesis; Pathway interactions; Patients; Pediatric Hospitals; Pennsylvania; Philadelphia; Pluripotent Stem Cells; Predisposition; Production; Recovery; Research; Research Personnel; Sampling; Science; Skin; Structure; Techniques; Technology; Testing; Time; Tissue Banks; Tissue Sample; Tissues; University Hospitals; Variant; Work; Zinc Fingers; base; clinically significant; cohort; cytokine; exome sequencing; genetic evolution; genetic manipulation; improved; induced pluripotent stem cell; insight; leukemia; monocyte; multidisciplinary; novel; novel therapeutic intervention; outcome forecast; patient population; peripheral blood; progenitor; public health relevance; repository; response; sample collection; skills; stem cell biology; success; tool

Our multidisciplinary team of clinicians and researchers seeks novel patient-individualized approaches for understanding and managing pediatric acquired aplastic anemia (aAA), a rare but devastating condition characterized by bone marrow hematopoietic stem cell (HSC) hypoplasia with life threatening bleeding, anemia and infections. Pediatric aAA is believed to occur via immune cell attack of HSCs, but little more is known about the pathogenesis and current treatments are not mechanism-based. Some patients with aAA develop clonal hematopoiesis, which is typically viewed pessimistically as a sign of impending myelodysplasia or leukemia. However, this may not always be the case, as our preliminary studies have identified numerous aAA patients with clonal hematopoiesis who have been in healthy remission for years. Moreover, many of these patients harbor unique mutations within their dominant hematopoietic clones. Thus, we hypothesize that clonal hematopoeisis in aAA results from mutational events that impart a growth or survival advantage to HSCs or early progenitors, particularly in the face of disease-associated insults. We will use modern genomic approaches to define the scope of these mutations in a large cohort of aAA patients (Aim 1), follow the clinical course and genetic evolution of the patients longitudinally (Aim 2). Several unique aspects of our study enhance its likelihood of success: First, we are a team of investigators with broad, synergistic expertise in the clinical management of aAA, bioinformatics and genomics/genetics. The ability to follow all of the patients longitudinally in a comprehensive pediatric-adult bone marrow failure clinic at The Children's Hospital of Philadelphia and The Hospital of the University of Pennsylvania. Finally, our study will utilize a large clinically well-annotated tissue collection obtained serially from over 100 aAA patients over 13 years, consisting of DNA and cryopreserved skin, blood and bone marrow cells. We will continue to follow these patients clinically and procure additional samples throughout the study. If successful, our work will identify sets of genes and gene mutations that will sub-classify aAA molecularly to predict prognosis more accurately and to identify more effective, mechanism-based patient-specific therapies.

我们由临床医生和研究人员组成的多学科团队寻求新颖的患者鉴定方法来理解和管理儿科获得的植物性贫血（AAA），这是一种罕见但毁灭性的疾病，其特征是骨髓造血性干细胞（HSC）下降症，并具有威胁生命的出血，障碍，障碍，障碍，障碍，障碍。据信小儿AAA是通过HSC的免疫细胞发作而发生的，但是关于发病机理和当前治疗不是基于机制的知识。一些AAA患者患有克隆造血，通常在悲观上被视为即将发生骨髓增生或白血病的标志。但是，情况并非总是如此，因为我们的初步研究已经确定了许多多年来健康缓解的克隆造血病患者。 此外，这些患者中有许多具有独特的造血克隆中的独特突变。 因此，我们假设AAA中的克隆血肿是由于突变事件引起的，这些事件赋予了HSC或早期祖细胞的生长或生存优势，尤其是面对疾病相关的损伤。我们将使用现代基因组方法来定义大量AAA患者队列中这些突变的范围（AIM 1），遵循纵向患者的临床过程和遗传进化（AIM 2）。我们研究的几个独特方面增强了成功的可能性：首先，我们是一个研究人员的团队，在AAA，生物信息学和基因组学/遗传学的临床管理方面具有广泛，协同的专业知识。在费城儿童医院和宾夕法尼亚大学医院的综合儿科骨髓衰竭诊所中，能够纵向关注所有患者。 最后，我们的研究将利用13年内从100多名AAA患者串行获得的大型临床通知的组织收集，包括DNA和冷冻保存的皮肤，血液和骨髓细胞。 我们将继续在临床上跟踪这些患者，并在整个研究过程中采购其他样本。 如果成功的话，我们的工作将确定一组基因和基因突变，这些基因和基因突变将对AAA分子进行亚分类，以更准确地预测预后，并确定更有效的，基于机制的患者特异性疗法。