Human Herpesvirus 6 in Lower Respiratory Tract Disease and Chromosomal Integration after Hematopoietic Cell Transplantation

人类疱疹病毒6型下呼吸道疾病及造血细胞移植后染色体整合

基本信息

批准号：
8948844
负责人：
Joshua Aiden Hill
金额：
$ 17.64万
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：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8948844
关键词：
Acute Graft Versus Host Disease Address Affect Allogenic Archives Benign Biological Preservation Biology Biometry Blood Blood Tests Bronchoalveolar Lavage Fluid Cell Transplants Cells Characteristics Clinical Clinical Research Collection Communicable Diseases Cytomegalovirus DNA Databases Detection Development Diagnostic Diagnostic Procedure Disease Ensure Epidemiology Etiology Foundations Functional disorder Future Gene Expression Gene Expression Profile Gene Expression Profiling General Population Genes Genetic Transcription Genome Goals Hematopoietic Hepatitis Human Chromosomes Human Herpesvirus 6 Immune response Immunocompromised Host Individual Infection Infectious Disease Epidemiology Knowledge Laboratories Link Lower respiratory tract structure Lung Medicine Mentors Methodology Methods Molecular Molecular Diagnostic Techniques Molecular Profiling Molecular Virology Morbidity - disease rate Organ Outcome Oxygen Pathogenesis Pathogenicity Pathologic Pathology Patient risk Patient-Focused Outcomes Patients Pharmaceutical Preparations Population Prevention Process Prospective Studies RNA Records Research Research Personnel Research Training Respiratory Tract Diseases Retrospective Studies Reverse Transcription Risk Risk Factors Role Sampling Source Stratification Structure of parenchyma of lung Techniques Testing Therapeutic Tissues Toxic effect Training Training Programs Transcript Transplant Recipients Viral Virus Virus Diseases Whole Blood base biobank career clinically significant cohort design differential expression hematopoietic cell transplantation improved innovation mortality novel pathogen programs prospective public health relevance screening secondary outcome statistics success tool transcriptome sequencing treatment strategy treatment trial virology

项目摘要

DESCRIPTION (provided by applicant): This proposal describes a five-year research training program that will allow Dr. Hill to achieve his long-term goal of becoming an independent clinically-oriented academic researcher, focusing on viral infections in immunocompromised hosts. Dr. Hill's goal is to improve hematopoietic cell transplantation (HCT) outcomes by advancing understanding of diseases associated with human herpesvirus 6 (HHV-6) and other viruses. He will apply this knowledge to develop diagnostic techniques and therapeutic strategies that mitigate complications due to viral infections in immunocompromised hosts. This proposal builds upon his clinical training in infectious diseases and methodology for clinical research in this field. Dr. Hill provides a detailed plan to improve his knowledge of advanced epidemiology, biostatistics, molecular virology, and conducting prospective studies. This proposal incorporates the expertise of an outstanding group of mentors, including experts in infectious diseases, epidemiology, laboratory medicine, pathology, and statistics, who are dedicated to ensuring the success of this project and the development of Dr. Hill's career as an independent clinical researcher. The first aim of this proposal involves a large retrospective study to determine the clinical significance of HHV- 6 in lower respiratory tract disease (LRTD) after HCT. Dr. Hill will test archived bronchoalveolar lavage fluid (BALF) for HHV-6 DNA with quantitative PCR. Based on these results, review of patient records, and molecular testing of blood and lung tissue, he will describe the epidemiology, risk factors, and clinical impact of HHV-6 in HCT recipients with LRTD. His second aim will employ prospective collection and processing of BALF and whole blood for viral and host gene expression studies using reverse transcription PCR and RNA- seq, respectively. These results will further characterize the molecular pathogenesis of HHV-6, inform the significance of HHV-6 DNA detection, and facilitate patient risk-stratification. The third aim will capitalize on novel molecular techniquesto identify and study a large retrospective cohort of HCT recipients with chromosomally integrated HHV-6, a poorly understood condition affecting 1-2% of the general population. While generally believed to be benign, preliminary evidence suggests that chromosomally integrated HHV-6 can be the source of pathologic HHV-6 reactivation and may warrant routine pre-HCT screening. Through accomplishing the aims in this proposal, Dr. Hill will address critical gaps in our knowledge of the importance of HHV-6 infection in HCT recipients and our ability to use clinical characteristics and novel molecular diagnostics to predict disease. Given that effective but potentially toxic medications are available to treat HHV-6, a better understanding of this virus will provide the basis to develop diagnostic, prevention, and treatment strategies. Ultimately, thi proposal will allow Dr. Hill to build a larger research program to advance understanding of viral infections in immunocompromised hosts and improve patient outcomes.

描述（由申请人提供）：该提案描述了一项为期五年的研究培训计划，该计划将使 Hill 博士实现成为一名独立的临床导向学术研究人员的长期目标，重点研究免疫功能低下宿主的病毒感染。 Hill 的目标是通过增进对人类疱疹病毒 6 (HHV-6) 和其他病毒相关疾病的了解来改善造血细胞移植 (HCT) 的结果。他将应用这些知识来开发减轻并发症的诊断技术和治疗策略。该提案建立在他在传染病方面的临床培训和该领域的临床研究方法的基础上，提供了一个详细的计划，以提高他在高级流行病学、生物统计学、分子病毒学方面的知识，并进行前瞻性研究。该提案融合了一批杰出导师的专业知识，其中包括传染病、流行病学、实验医学、病理学和统计学方面的专家，他们致力于确保该项目的成功以及希尔博士职业生涯的发展。该提案的第一个目标是开展一项大型回顾性研究，以确定 HCT 后 HHV-6 在下呼吸道疾病 (LRTD) 中的临床意义，Hill 博士将对存档的支气管肺泡灌洗液 (BALF) 进行 HHV- 检测。 6 DNA 定量 PCR 基于这些结果、患者记录审查以及血液和肺组织的分子检测，他将描述 HHV-6 对 HCT 受者的流行病学、危险因素和临床影响。 LRTD 的第二个目标是分别使用逆转录 PCR 和 RNA-seq 前瞻性收集和处理 BALF 和全血，用于病毒和宿主基因表达研究。这些结果将进一步表征 HHV-6 的分子发病机制，并揭示其重要性。第三个目标是利用新的分子技术来识别和研究大量患有染色体整合 HHV-6 的 HCT 接受者，这是一种影响 1-2% 的疾病，人们对此知之甚少。虽然普遍认为是良性的，但初步证据表明，染色体整合的 HHV-6 可能是病理性 HHV-6 重新激活的根源，并且可能需要进行常规 HCT 筛查。 Hill 将解决我们对 HHV-6 感染对 HCT 接受者的重要性的认识以及我们利用临床特征和新颖的分子诊断来预测疾病的能力方面的关键差距。鉴于有效但具有潜在毒性的药物可用于治疗 HHV-6，更好地了解这种病毒将为制定诊断、预防和治疗策略奠定基础，该提案将使希尔博士能够建立一个更大的研究计划，以增进对免疫功能低下宿主的病毒感染的了解并改善患者的治疗结果。