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: 9923750
• 负责人: Benjamin Watkins
• 金额: $ 13.89万
• 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/9923750
• 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; experience; experimental study; immunoprophylaxis; immunoregulation; improved; insight; mortality; nonhuman primate; novel; novel strategies; novel therapeutic intervention; patient stratification; phase II trial; post-transplant; prevent; 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.

项目概要： 异基因造血干细胞移植（HCT）是治疗血液病的有效方法。 恶性肿瘤，然而它与限制其应用的严重并发症有关。 宿主疾病（CGVHD）是 HCT 和近期 HCT 后长期发病率和死亡率的主要原因 进展未能对其发生频率或严重程度产生重大影响。 CGVHD 的发展和演变尚未明确定义，使得新治疗方法的设计 旨在预防或治疗具有挑战性的疾病的方法。 分析已成为询问复杂疾病状态和定义分子变化的宝贵工具 利用这些方法来识别疾病发展过程中发生的机械驱动因素。 CGVHD 的研究将极大地帮助我们了解该疾病并帮助阐明可靶向的途径 改变其自然历史。 为了确定 GVHD 的驱动机制，我们的小组开发了一种系统生物学方法， 拟议的研究项目将应用这些技术，将流式细胞术与基因表达分析相结合。 监督和非监督方法来确定与 T 细胞和 B 细胞相关的分子特征 CGVHD 的发展和演变。拟议的工作将利用我们精心策划的生物存储库。 随机、安慰剂对照 II 期临床试验正在研究阿巴西普 (CTLA4-Ig)。 一种新型 GVHD 预防剂，并将提供与生物制剂相关的详细临床数据 目标 1 将寻求鉴定与发育相关的 T 细胞和 B 细胞基因以及通路。 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。 目标 2 将寻求通过识别 T 细胞和 B 细胞基因来解决阿巴西普对 CGVHD 的影响， 阿巴西普治疗患者中与 CGVHD 相关的通路并比较相关分子 未接受阿巴西普治疗的 CGVHD 患者发生的变化 完成这些。 目标将显着增加我们对 CGHVD 的发展和演变的理解，并希望 提供创建 CGVHD 预防风险适应方法所需的数据。 深入研究阿巴西普的作用机制并揭示突破性 CGVHD 发生的方法。 沃特金斯博士结合他的经验和职业生涯，确定了一支出色的指导团队 开发计划有望取得成功，沃特金斯博士将从中受益匪浅。 埃默里大学的支持性研究环境和临床试验方法的正式培训 K23 提供的结构和支持将巩固他在临床研究方面的技能。 促进沃特金斯博士成为一名成功的独立医师科学家和该领域的领导者 CGVHD。