Characterizing the molecular signature of chronic graft-versus-host disease following hematopoietic stem cell transplantation

造血干细胞移植后慢性移植物抗宿主病的分子特征特征

• 批准号: 10394036
• 负责人: Benjamin Watkins
• 金额: $ 6.35万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-01-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394036
• 关键词: Acute Graft Versus Host Disease; Address; Adopted; Allogenic; Automobile Driving; B-Lymphocyte Subsets; B-Lymphocytes; Bioinformatics; Biological; CTLA4-Ig; Cell physiology; Cessation of life; Clinical; Clinical Data; Clinical Research; Clinical Trials; Complex; Coupled; Data; Development; Development Plans; Disease; Environment; Evolution; Flow Cytometry; Frequencies; Gene Expression Profiling; Genes; Goals; Hematologic Neoplasms; Hematological Disease; Hematopoietic Stem Cell Transplantation; Immune; Inflammatory; Laboratories; Laboratory Study; Link; Malignant - descriptor; Mediating; Mediator of activation protein; Mentors; Methodology; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Multiparametric Analysis; Natural History; Non-Malignant; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phase; Phase II Clinical Trials; Phenotype; Physicians; Placebos; Population; Prevention; Prevention strategy; Process; Randomized; Research; Research Project Grants; Resources; Risk; Sampling; Scientist; Severities; Structure; Supervision; System; Systems Biology; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic Intervention; Toxic effect; Training; Translations; Transplantation; Universities; Work; biobank; career development; chronic graft versus host disease; cohort; design; disorder prevention; effective therapy; efficacy evaluation; experience; experimental study; immunoprophylaxis; immunoregulation; improved; insight; mortality; nonhuman primate; novel; novel strategies; novel therapeutic intervention; patient stratification; phase II trial; post-transplant; prevent; risk stratification; skills; therapeutic development; tool; transcriptome; transcriptomics; treatment strategy

Project Summary: Allogeneic hematopoietic stem cell transplantation (HCT) is an effective treatment for hematological malignancy, however it is associated with significant complications limiting its application. Chronic graft-versus- host disease (CGVHD) is the leading cause of long-term morbidity and mortality following HCT and recent advances have failed to make a significant impact on its frequency or severity. The mechanisms of the development and evolution of CGVHD have not been clearly defined making the design of new therapeutic approaches aimed at preventing or treating the disease challenging. Flow cytometry and gene expression profiling have become valuable tools to interrogate complex disease states and define the molecular changes that occur during the development of disease. Utilizing these approaches to identifying the mechanistic drivers of CGVHD would aid significantly in our understanding of the disease and help elucidate targetable pathways to alter its natural history. To identify the mechanisms driving GVHD, our group has developed a systems biology approach that combines flow cytometry with gene expression analysis. The proposed research project will apply these supervised and unsupervised approaches to determine the molecular signature of T and B cells linked to the development and evolution of CGVHD. The proposed work will utilize the highly curated biorepository of our clinical trial. The randomized, placebo-controlled phase II clinical trial is investigating abatacept (CTLA4-Ig) as a novel GVHD prevention agent and will provide detailed clinical data that will be linked to the biologic samples. Aim 1 will seek to identify the T and B cell genes and pathways associated with the development and evolution of CGVHD and determine if the molecular changes can be used to risk-stratify patients at day 100. Aim 2 will seek to address the impact of abatacept on CGVHD by identifying the T and B cell genes and pathways associated with CGVHD in abatacept treated patients and compare the associated molecular changes to the changes that occur in patients with CGVHD not exposed to abatacept. Completion of these aims will add significantly to our understanding of the development and evolution of CGHVD and hopefully provide the data necessary to create a risk-adapted approach to CGVHD prevention. It will also provide insight into the mechanism of action of abatacept and reveal the means of the breakthrough CGVHD that occurs. Dr. Watkins has identified an exceptional mentoring team and in combination with his experience and career development plan is poised to succeed with his proposed research plan. Dr. Watkins will benefit greatly from the supportive research environment of Emory University and the formal training in clinical trial methodology and bioinformatics will solidify his skills in clinical research. The structure and support provided by the K23 will facilitate Dr. Watkins’ translation into a successful independent physician scientist and a leader in the field of CGVHD.

项目摘要： 异基因造血干细胞移植（HCT）是治疗血液病的有效方法。 然而，它与限制其应用的显著并发症相关。慢性移植物抗 宿主病（CGVHD）是HCT后长期发病和死亡的主要原因， 这些进展未能对其发生频率或严重程度产生重大影响。各机制 CGVHD的发展和演变尚未明确定义，使得新的治疗方案的设计 旨在预防或治疗具有挑战性的疾病的方法。流式细胞术和基因表达 谱分析已经成为询问复杂疾病状态和确定分子变化的有价值的工具 在疾病发展过程中发生的变化。利用这些方法来识别机械驱动因素 CGVHD的诊断将大大有助于我们对疾病的理解，并有助于阐明靶向途径。 来改变它的自然历史 为了确定驱动GVHD的机制，我们的团队开发了一种系统生物学方法， 结合流式细胞术和基因表达分析。该研究项目将应用这些 有监督和无监督的方法来确定T和B细胞的分子特征， CGVHD的发展和演变。拟议的工作将利用我们的高度策展的生物储存库 临床试验这项随机、安慰剂对照的II期临床试验正在研究阿巴西普（CTLA 4-IG）作为 一种新的GVHD预防剂，并将提供详细的临床数据，将与生物 样品目的1将寻求鉴定与发育相关的T和B细胞基因和途径， CGVHD的演变，并确定分子变化是否可用于在第100天对患者进行风险分层。 目的2将寻求通过鉴定T和B细胞基因来解决阿巴西普对CGVHD的影响， 在阿巴西普治疗的患者中与CGVHD相关的途径，并比较相关的分子 与未暴露于阿巴西普的CGVHD患者中发生的变化相比的变化。完成这些 这些目标将大大增加我们对CGHVD发展和演变的理解， 提供必要的数据，以创建一个适应风险的方法来预防CGVHD。它还将提供洞察力 阿巴西普的作用机制，并揭示发生突破CGVHD的手段。 博士沃特金斯已经确定了一个特殊的指导团队，并结合他的经验和职业生涯 他提出的研究计划将使发展计划取得成功。沃特金斯博士将受益匪浅 埃默里大学的支持性研究环境和临床试验方法学的正式培训 生物信息学将巩固他在临床研究方面的技能。K23提供的结构和支撑将 促进沃特金斯博士的翻译成一个成功的独立的医生科学家和领导者在该领域的 CGVHD。