Mentoring Junior Faculty: Viral hepatitis Clinical Research

描述（由申请人提供）：慢性病毒性肝炎是全球发病率和死亡率的主要原因。在过去十年中，慢性丙型肝炎和乙型肝炎的新治疗方法的开发取得了重大进展，尽管这些疾病的管理策略仍在不断发展。半数以上接受聚乙二醇干扰素和利巴韦林治疗的慢性丙型肝炎患者可获得持续的病毒学应答。然而，许多患者仍然无法实现永久的病毒根除，或者由于医学或社会心理合共病而不适合初始抗病毒治疗，这些合共病是聚乙二醇干扰素和利巴韦林治疗的禁忌症。相比之下，以核苷类似物治疗慢性乙型肝炎为例，其耐受性更好，尽管疗效通常是通过延长病毒抑制时间而不是永久治愈来衡量的。对于这两种疾病，更好地了解治疗反应减弱的机制，开发优化的治疗方案，和/或确定替代或新型药物是至关重要的。北卡罗来纳大学肝病项目在Michael Fried博士的指导下，非常积极地从事慢性病毒性肝炎治疗方面的研究。为了本次申请的目的，我们将讨论一项正在进行的I/II期研究，该研究由NCCAM/NIDDK资助，研究水飞蓟素（水飞蓟）作为传统抗病毒治疗无效的慢性丙型肝炎患者的替代治疗方法（U01-AT003560, SyNCH）。此外，我们将回顾由NIDDK （U01 DK082867）资助的一项针对慢性乙型肝炎的新研究——乙型肝炎临床研究网络。最后，我们将详细介绍一项研究者发起的研究，该研究利用新方法检查外周血单个核细胞中的干扰素信号通路。这些研究为积极参与其设计、实施和分析的初级教师和研究员提供了指导计划的支柱。正如本应用程序中所展示的，学员已经被整合到这些研究活动中，这些研究活动为他们提供了许多机会，在一个有指导的环境中，他们可以发展研究技能，并坚持自己对单个项目的所有权。

DESCRIPTION (provided by applicant): Chronic viral hepatitis is a major global cause of morbidity and mortality. Over the last decade, significant progress has occurred in the development of new treatments for chronic hepatitis C and hepatitis B, although management strategy of these diseases continues to evolve. More than half of patients undergoing treatment with peginterferon and ribavirin for chronic hepatitis C can achieve a sustained virological response. However, numerous patients still fail to achieve permanent viral eradication or are not candidates for initial antiviral therapy due to medical or psychosocial comorbidities which are contraindications to peginterferon and ribavirin therapy. In contrast, treatments for chronic hepatitis B with nucleoside analogues, as examples, are better tolerated, although efficacy is generally measured by prolonged viral suppression, rather than permanent cure. For both these diseases, a better understanding of mechanisms of diminished response to therapy, development of optimized treatment regimens, and/or the identification of alternative or novel medications is of critical importance. The UNC Liver Diseases Program, under the direction of Dr. Michael Fried, is extremely active in pursuing studies that focus on treatment of chronic viral hepatitis. For the purposes of this application, we will discuss an ongoing phase I/II study, funded by NCCAM/NIDDK, that investigates silymarin (milk thistle) as an alternative treatment for patients with chronic hepatitis C who failed to respond to conventional antiviral therapy (U01-AT003560, SyNCH). Furthermore, we will review a new study for chronic hepatitis B, the Hepatitis B Clinical Research Network, funded by NIDDK (U01 DK082867). Finally, we will present a detailed synopsis of an investigator initiated study that examines interferon signaling pathways in peripheral blood mononuclear cells utilizing novel methodologies. These studies provide the backbone of the mentoring program for junior faculty and fellows who are actively involved in their design, implementation, and analysis. As demonstrated within this application, mentees have been integrated into these research activities which have provided them with numerous opportunities in a mentored environment within which to develop research skills and to assert their ownership of individual projects. PUBLIC HEALTH RELEVANCE: In this competing renewal application for the K24 Mentoring Award, I will provide detailed information regarding my background in patient-oriented research and the successful clinical research and integrated mentoring program that has been developed directly as a result of this award. I will also demonstrate my continued dedication to clinical research and to a diverse group of talented junior investigators for whom I serve as primary mentor. Finally, we will provide examples of several new research initiatives that will continue to ensure effective mentored research opportunities, as well as a plan for the development of interdisciplinary research teams capable of performing translational research studies.