Biomarker Discovery in Chronic Graft-vs-Host Disease

慢性移植物抗宿主病的生物标志物发现

• 批准号: 7881588
• 负责人: John Andrew Hansen
• 金额: $ 44万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-17 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7881588
• 关键词: Address; Allogenic; Alternative Splicing; Ancillary Study; Antibodies; Biological Assay; Biological Markers; Candidate Disease Gene; Caring; Case-Control Studies; Chronic; Clinical; Clinical Trials; Cohort Studies; Consent; Consent Forms; Dana-Farber Cancer Institute; Development; Diagnosis; Diagnostic; Disease; Effectiveness; Enrollment; Exons; Family; Fred Hutchinson Cancer Research Center; Funding; Gene Expression; Goals; Grant; Health care facility; Hematopoietic Stem Cell Transplantation; Human; Immunosuppression; Letters; Mass Spectrum Analysis; Methods; Minnesota; Modification; Monitor; Mononuclear Leukocytes; Morbidity - disease rate; Outcome Assessment; Participant; Patients; Peripheral Blood Mononuclear Cell; Phase; Physicians; Plasma; Proteins; Proteomics; Protocols documentation; Research Ethics Committees; Research Personnel; Resolution; Sampling; Sampling Studies; Sensitivity and Specificity; Severities; Site; Staging; Study Subject; Survivors; Symptoms; Therapeutic Intervention; United States National Institutes of Health; Universities; Validation; Variant; abstracting; base; cancer care; candidate validation; chronic graft versus host disease; disorder control; genome wide association study; genome-wide analysis; graft vs host disease; improved; innovative technologies; insight; mortality; novel; peripheral blood; response; sample collection; tool; treatment response; treatment strategy; validation studies; willingness

DESCRIPTION (provided by applicant): Chronic graft-versus-host disease (cGVHD) occurs in 50-70% of patients following allogeneic hematopoietic stem cell transplantation (HSCT) and is a major cause of morbidity and mortality. The clinical manifestations of cGVHD are diverse and variable, and the diagnosis, staging and assessment of response to therapeutic interventions have been difficult to standardize. There are no signs or symptoms or diagnostic tools that predict the development or severity of cGVHD, or the need for immune suppression therapy. The goal of this proposal is to address these unmet needs by identifying novel biomarkers that are associated with the onset and severity of cGVHD. The initial phase of study will consist of a parallel discovery strategy that employs a genome-wide analysis of transcriptional changes in peripheral blood mononuclear cells (PBMC) together with a high-resolution, high-sensitivity quantitative proteomic analysis to identify informative proteins in plasma that correlate with disease activity. These transcriptional changes and proteins will be prioritized to develop a list of candidates for second phase validation studies to confirm and further define a panel of markers that together provide high sensitivity and specificity for the diagnosis of cGVHD and the prediction of severity and/or treatment response. Aim 1 of this study is to identify novel biomarkers in peripheral blood for the diagnosis of cGVHD using dual approaches: 1a) analysis of global gene expression and alternate splicing in mononuclear leucocytes; and 1b) quantitative in-depth profiling of circulating proteins in plasma. The transcriptional analysis will be performed on PBMC using the Affymetrix Human Exon 1.0 ST array, and the proteomic analysis will be performed on plasma by mass spectrometry. Aim 2 will focus on the validation of candidate biomarkers identified in an independent, multicenter cohort study of cGVHD. Candidate genes and alternate splice variants will be validated by PCR-based assays, and candidate proteins will be validated by antibody-based assays. This application is submitted in response to RFA-HL-08-001, titled "Ancillary Studies in Clinical trials (R01)." We are proposing a biomarker discovery and validation project that is focused on cGVHD occurring after allo HSCT. The subjects for this study, cases and controls, will be enrolled in a separate NIH funded multi-center study titled "Improving outcomes assessment in chronic GVHD" (R01-CA118953; Dr. Stephanie Lee, PI). Participating Centers include the Dana-Farber Cancer Institute (DFCI), the Seattle Cancer Care Alliance (SCCA)/Fred Hutchinson Cancer Research Center (FHCRC), Stanford University and the University of Minnesota. Total enrollment across the sites will reach 336 incident and 336 prevalent cGVHD cases. Patients will be followed for three years, and systematically evaluated for cGVHD status and response to cGVHD therapy. Chronic graft-versus-host disease (cGVHD) occurs in 50-70% of patients following allogeneic hematopoietic stem cell transplantation (HSCT) and is a major cause of morbidity and mortality. As the utilization of HSCT and number of HSCT survivors increases, the issue of cGVHD becomes a greater concern not only to patients and their families but also to the specialized physicians and health care facilities responsible for their care. The studies proposed here are aimed at improving methods for the diagnosis of cGVHD, monitoring disease activity and the effectiveness of cGVHD therapy. These studies may also yield insights into the underlying disorders responsible for cGVHD and thereby suggest new treatment strategies. (End of Abstract)

描述(由申请人提供)： 慢性移植物抗宿主病(CGVHD)发生在异基因造血干细胞移植(HSCT)后50-70%的患者，是导致发病率和死亡率的主要原因。慢性移植物抗宿主病的临床表现多种多样，其诊断、分期和治疗效果的评估一直难以标准化。没有任何迹象、症状或诊断工具可以预测cGVHD的发展或严重程度，或是否需要免疫抑制治疗。这项提案的目标是通过确定与cGVHD的发病和严重程度相关的新生物标记物来解决这些未得到满足的需求。研究的初始阶段将包括并行发现策略，该策略采用外周血单个核细胞(PBMC)转录变化的全基因组分析，以及高分辨率、高灵敏度的定量蛋白质组分析，以确定血浆中与疾病活动相关的信息蛋白质。这些转录变化和蛋白质将被优先考虑，以制定第二阶段验证研究的候选名单，以确认并进一步定义一组标记，这些标记共同为cGVHD的诊断和严重程度和/或治疗反应的预测提供高敏感性和特异性。本研究的目的1是利用两种方法在外周血中寻找新的诊断cGVHD的生物标志物：1a)分析单个核白细胞的整体基因表达和交替剪接；1b)定量深入分析血浆中循环蛋白。转录分析将使用Affymetrix Human Exon 1.0 ST阵列在PBMC上进行，蛋白质组学分析将在血浆中通过质谱仪进行。目标2将侧重于在cGVHD的独立多中心队列研究中确定的候选生物标记物的验证。候选基因和备选剪接变体将通过基于聚合酶链式反应的分析来验证，候选蛋白质将通过基于抗体的分析来验证。本申请是根据RFA-HL-08-001，题为“临床试验中的辅助研究(R01)”提交的。我们正在提出一个生物标记物的发现和验证项目，该项目专注于allo HSCT后发生的cGVHD。这项研究的受试者，病例和对照，将被纳入一项由美国国立卫生研究院资助的单独的多中心研究，题为“改善慢性GVHD的结果评估”(R01-CA118953；Dr.Stephanie Lee，PI)。参与中心包括达纳-法伯癌症研究所(DFCI)、西雅图癌症护理联盟(SCCA)/弗雷德·哈钦森癌症研究中心(FHCRC)、斯坦福大学和明尼苏达大学。所有网站的注册总人数将达到336例突发事件和336例cGVHD流行病例。患者将被跟踪三年，并系统地评估cGVHD状态和对cGVHD治疗的反应。慢性移植物抗宿主病(CGVHD)发生在异基因造血干细胞移植(HSCT)后50-70%的患者，是导致发病率和死亡率的主要原因。随着造血干细胞移植的使用率和移植幸存者数量的增加，cGVHD问题不仅成为患者及其家人的关注问题，而且也成为负责护理他们的专科医生和卫生保健机构的关注焦点。这些研究旨在改进cGVHD的诊断方法、监测疾病活动性和cGVHD治疗的有效性。这些研究还可能对cGVHD的潜在疾病有深入的了解，从而提出新的治疗策略。(摘要结束)