Genetic Analysis of Airflow Obstruction After Stem Cell Transplantation

干细胞移植后气流阻塞的遗传分析

基本信息

批准号：
7619610
负责人：
JASON W CHIEN
金额：
$ 44万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7619610
关键词：
Affect Allogenic Asthma Biological Markers Bone Marrow Transplantation Bronchiolitis Obliterans Cell Transplants Cessation of life Chest Chronic Obstructive Airway Disease Clinical Clinical Data Clinical Research Complement Complex Complication DNA Data Development Devices Disease Electronics Epidemiologic Studies Evaluation Future Genes Genetic Genetic Markers Genetic Variation Goals Hematopoietic Image Immunity Inflammatory Long-Term Survivors Lung Matrix Metalloproteinases Measurement Metalloproteinase Gene Modeling Monitor Natural Immunity Nature Obstruction Pathogenesis Pathway interactions Patients Phase II Clinical Trials Phenotype Population Protocols documentation Quality of life Respiratory physiology Retrospective Studies Risk Specimen Stem cell transplant Symptoms Syndrome Transplantation Validation Work base chemokine clinical phenotype cohort diaries genetic analysis genetic association genetic variant graft vs host disease human leukocyte antigen gene insight new therapeutic target prospective public health relevance pulmonary function

项目摘要

DESCRIPTION (provided by applicant): Severe airflow obstruction (AFO) was first recognized in the early 1980s as a serious and often fatal complication of bone marrow transplantation. Known as bronchiolitis obliterans syndrome in its severest form, this syndrome is now estimated to affect up to 26% of patients who receive an allogeneic hematopoietic cell transplant (HCT), representing the most common pulmonary complication among long-term survivors. While epidemiologic studies suggest HCT-related AFO is a form of graft versus host disease (GVHD) in the lung resulting from alloreactivity, these same studies have also indicated the risk attributable to GVHD is less than anticipated, suggesting other variables likely influence the risk of developing HCT-related AFO. Preliminary genetic studies that we have conducted indicate that genetic variation in the innate immunity pathway significantly influences the risk of developing this complication. However, given the complex nature of this phenotype, it is likely there are many other pathways involved in the pathogenesis of HCT-related AFO. We hypothesize that genetic variants in key biologic pathways involved in the development of HCT-related AFO significantly influences the risk for developing this syndrome. The primary goal of this proposal is to identify these genetic variants and document their clinical utility as biomarkers in the management of patients at risk for developing HCT-related AFO. In Specific Aim 1, using a discovery and validation cohort, we will conduct a tagSNP based genetic association study to systematically screen innate immunity, adaptive immunity, chemokine, remodeling, and matrix metalloproteinase genes to identify a panel of genetic variants that are most informative for predicting the risk of developing HCT-related AFO. In Specific Aim 2, we will implement a patient directed protocol for monitoring lung function in a prospective cohort to characterize in detail the HCT-related AFO clinical phenotype. This protocol will prospectively characterize the clinical profile HCT-related AFO and provide a prospective validation cohort that will overcome the limitations of retrospective studies. Finally, we will use the genetic data from Aim 1 to identify a highly informative panel of genetic markers that will be predictive of this well-characterized phenotype. These genetic markers will also be combined with pretransplant clinical predictors of AFO to develop a predictor model that can identify patients at risk for developing HCT-related AFO accurately. These studies will result in genetic biomarkers useful for identifying populations for future phase II clinical trials, provide new insights into the disease pathobiology, and serve as novel therapeutic targets. These findings will also be applicable to other airways diseases such as asthma, COPD, and bronchiolitis obliterans after lung transplant. PUBLIC HEALTH RELEVANCE: The primary goal of this proposal is to identify these genetic variants and document their clinical utility as biomarkers in the management of patients at risk for developing HCT related AFO. We hypothesize that genetic variants in key biologic pathways involved in the development of airways diseases likely influence the risk of developing HCT-related AFO and when identified, will reveal key biologic mechanisms by which this syndrome occurs.

描述（由申请人提供）：严重的气流阻塞（AFO）首先在1980年代初被认为是骨髓移植的严重且经常致命的并发症。现在，该综合征被称为最严重形式的支气管炎闭塞性综合征，据估计，该综合征会影响多达26％的接受同种异体造血细胞移植（HCT）的患者，这代表了长期幸存者中最常见的肺并发症。虽然流行病学研究表明与HCT相关的AFO是同种反应性引起的肺中的一种移植物与宿主疾病（GVHD）的一种形式，但这些相同的研究也表明，GVHD归因于GVHD的风险远低于预期，这表明其他变量可能会影响与HCT降低的AFO的风险。我们已经进行的初步遗传研究表明，先天免疫途径的遗传变异显着影响发展这种并发症的风险。但是，鉴于该表型的复杂性质，与HCT相关的AFO发病机理中可能还有许多其他途径。我们假设与HCT相关AFO开发的关键生物学途径中的遗传变异显着影响发展该综合征的风险。该提案的主要目的是确定这些遗传变异，并记录其临床实用性，作为在患者患有HCT相关AFO风险的患者管理中的生物标志物。在特定的目标1中，使用发现和验证队列，我们将进行基于TAGSNP的遗传关联研究，以系统地筛选先天免疫，适应性免疫，趋化因子，趋化因子，重塑和基质金属蛋白酶基因，以识别遗传变异的小组，这些遗传变体是最有用的，这些遗传变异是可预测开发Hct-act-proped Hct-proped Hct-proped Affo的风险。在特定的目标2中，我们将实施一种患者的指示方案，以监测前瞻性队列中的肺功能，以详细表征与HCT相关的AFO临床表型。该方案将前瞻性地表征与HCT相关的AFO，并提供前瞻性验证队列，以克服回顾性研究的局限性。最后，我们将使用来自AIM 1的遗传数据来确定一组高度信息的遗传标记，这些标记将预测这种良好的表征。这些遗传标记也将与AFO的移植前临床预测指标相结合，以开发一个预测模型，该模型可以准确地确定与HCT相关的患者的风险。这些研究将导致遗传生物标志物有助于确定未来II期临床试验的种群，为病理生物学提供新的见解，并充当新的治疗靶标。这些发现也将适用于其他气道疾病，例如肺移植后哮喘，COPD和细支气管炎。公共卫生相关性：该提案的主要目标是确定这些遗传变异，并记录其临床实用性，以作为管理与HCT相关的AFO风险的患者的生物标志物。我们假设在涉及呼吸道疾病发展的关键生物学途径中的遗传变异可能会影响发展与HCT相关的AFO的风险，并在鉴定出来时会揭示这种综合征发生的关键生物学机制。