Patient-Oriented Research on Hepatitis in Special Populations

以患者为中心的特殊人群肝炎研究

• 批准号: 8479347
• 负责人: RAYMOND T CHUNG
• 金额: $ 16.04万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8479347
• 关键词: AIDS clinical trial group; Algorithms; Allografting; Antiviral Agents; Applications Grants; Award; Back; Biological Markers; Cholesterol; Chronic Hepatitis C; Chronic viral hepatitis; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Cross-Sectional Studies; Data; Dependence; Development; Disease; Disease Management; Disease Progression; Disease susceptibility; Explosion; Faculty; Flavonoids; Foundations; Funding; Funding Agency; Genetic; Genetic Markers; Genomics; Grant; HCV Liver Disease; HIV; Hepatitis; Hepatitis B; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Institution; Investigation; Knowledge; Letters; Liver diseases; Mentors; Mentorship; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Other Genetics; Patients; Persons; Phase; Population; Prevention; Primary carcinoma of the liver cells; Process; Productivity; Publications; Research; Research Personnel; Role; Science; Secure; Source; Surveys; Technology; Testing; Therapeutic; Training; Translational Research; United States; United States National Institutes of Health; Veins; Viral; Viral hepatitis; Vulnerable Populations; Work; base; career; cohort; design; disease natural history; experience; innovation; liver transplantation; man; mortality; named group; naringenin; next generation; novel; patient oriented research; patient population; pilot trial; pre-clinical; prevent; programs; prospective; therapeutic target; translational medicine; translational study; viral liver disease

DESCRIPTION (provided by applicant): Chronic hepatitis C and B are important and growing causes of morbidity and mortality in the United States. In particular, a disproportionate burden of mortality is borne by groups with specific disease susceptibilities. These include patients with HIV coinfection and patients undergoing liver transplantation for HCV and HBV-related complications, both of whom experience accelerated natural history of disease. The basis for these observations is not well understood, but an increasing number of plausible hypotheses have been suggested by our preclinical work. As with the original submission of this application in the first cycle of this grant, this proposal demonstrates the candidate's track record of productivity and lengthy commitment to patient-oriented research in viral hepatitis and his record of mentorship in the development of junior faculty and fellows embarking on clinical and translational research careers in liver disease. Over the past grant cycle, Dr. Chung has fully followed through on the original aims of the proposal, which were to (1) mentor fellows and junior faculty in initiation of patient-oriented research careers in the study of HCV disease in special populations; and (2) initiate innovative pilot clinical trials in HCV based on key observations from our mechanistic work. During the first cycle of this Award, Dr. Chung has mentored over 20 Fellows and junior faculty, and many have secured NIH or foundation funding. The focus of the next cycle of Dr. Chung's program will be to integrate advances in the continuum of translational investigation into the training of the next generation of clinical researchers. These include the creation of disease cohorts, genomic and other discovery surveys of these cohorts, identification of biomarkers and therapeutic targets, development of novel therapies, application of these therapies in first in man proof of concept studies, application of biomarkers for use in disease prognostication and modeling. In this regard, Aim 1, development of clinical prediction models and disease management algorithms that incorporate fundamental discoveries such as genetic markers, will be an important focus for young clinical investigators in the next grant cycle, as will creation of novel disease cohorts, such as those with HBV-HIV coinfection. In Aim 2, advances in discovery will be tested in the therapeutic arena. These advances include our mechanistic work defining the dependence of HCV on cholesterol intermediates and the efficacy of statins in the viral lifecycle, along with our discovery that a flavonoid, naringenin, has antiviral effects against HCV secretion. This work will form the basis for design of innovative pilot clinical trials, including studies of agents to prevet allograft HCV infection, the most important source of mortality in persons undergoing liver transplantation (LT). In this vein, the PI's role as Vice Chair of the ACTG Hepatitis Transformative Science Group (TSG) will also enable the initiation of junior investigators in several exciting proof of concept studies testing novel combinations of direct acting antiviral agents and statins against HCV in both HIV(-) and HIV(+) hosts. Similarly, the PI's participation with the MGH Translational Medicine Group (TMG) will also permit engagement of junior investigators in translational studies of early phase compounds in special populations such as post-LT HCV. Collectively, these studies will offer rich opportunities for clinical investigators t be mentored as they enter the highly interdigitated continuum of translational investigation. In so doing, it is anticipated by Dr. Chung that they will themselves mentor their own fellows and faculty, thereby creating a highly desirable multiplier effect.

描述（由申请人提供）：慢性丙型肝炎和乙型肝炎是美国发病率和死亡率的重要且日益增长的原因。特别是，不成比例的负担 死亡率由具有特定疾病易感性的群体承担。这些患者包括 HIV 合并感染患者以及因 HCV 和 HBV 相关并发症而接受肝移植的患者，两者都经历了疾病自然史的加速。这些观察结果的基础尚不清楚，但我们的临床前工作提出了越来越多的合理假设。与本次资助的第一个周期中最初提交的申请一样，该提案展示了候选人的生产力记录和对病毒性肝炎以患者为导向的研究的长期承诺，以及他在初级教员和研究员的发展中的指导记录肝病的临床和转化研究生涯。在过去的资助周期中，钟博士完全遵循了该提案的最初目标，即（1）指导研究员和初级教师在特殊人群的丙型肝炎研究中开展以患者为导向的研究生涯； (2) 根据我们机制工作的关键观察结果启动 HCV 创新型试点临床试验。在该奖项的第一个周期中，钟博士指导了 20 多名研究员和初级教师，其中许多人获得了 NIH 或基金会的资助。 钟博士项目下一周期的重点是将连续转化研究的进展融入到下一代临床研究人员的培训中。其中包括创建疾病队列、对这些队列进行基因组和其他发现调查、识别生物标志物和治疗靶点、开发新疗法、将这些疗法应用于首次人体概念验证研究、将生物标志物用于疾病预测和建模。在这方面，目标 1，即开发结合遗传标记等基本发现的临床预测模型和疾病管理算法，将成为年轻临床研究人员在下一个拨款周期中的一个重要重点，同时创建新的疾病队列，例如HBV-HIV 合并感染者。在目标 2 中，发现的进展将在治疗领域得到检验。这些进展包括我们的机制工作，定义了 HCV 对胆固醇中间体的依赖性和他汀类药物在病毒生命周期中的功效，以及我们发现黄酮类柚皮素对 HCV 分泌具有抗病毒作用。这项工作将 形成创新试点临床试验设计的基础，包括预防同种异体移植物 HCV 感染的药物研究，HCV 感染是肝移植 (LT) 患者最重要的死亡来源。在这方面，PI 作为 ACTG 肝炎转型科学组 (TSG) 副主席的角色也将使初级研究人员能够启动几项令人兴奋的概念验证研究，测试直接作用抗病毒药物和他汀类药物在 HIV 和 HIV 中对抗 HCV 的新型组合。 (-) 和 HIV(+) 宿主。同样，PI 参与 MGH 转化医学小组 (TMG) 也将允许初级研究人员参与特殊人群（例如 LT 后 HCV）的早期化合物的转化研究。总的来说，这些研究将为临床研究人员提供丰富的机会，让他们在进入高度交叉的转化研究连续体时得到指导。在这样 在这样做的过程中，钟博士预计他们自己将指导自己的研究员和教师，从而产生非常理想的乘数效应。