Factors Responsible for Liver Recovery After Successful Treatment of Hepatitis C.

摘要 丙型肝炎病毒(丙型肝炎病毒)的治疗进展第一次创造了这样一种情况 患有非常严重疾病的患者很容易实现病毒学治愈。然而，初步迹象表明， 表明这些患者中多达三分之一的人将继续病情发展，尽管他们已经“治愈”了病毒。 哪些因素将决定病毒感染后患者的结局，从而决定最佳治疗， 晚期肝病在很大程度上是未知的。慢性丙型肝炎病毒感染与胰岛素抵抗和 脂肪变性，促进纤维化进展。我们推测与纤维化进展相关的因素 在活动性疾病期间与临床恢复和术后纤维化消退呈负相关 活动性疾病的消退。这一提议的中心假设是胰岛素的正常化 耐药和脂肪变性是丙型肝炎患者临床恢复和纤维化消退的核心 肝硬变，以及胰岛素反应和脂肪变性的遗传变异 原发病治疗后的异质性反应。我们将前瞻性地测试我们的 通过检查一大批慢性阻塞性肺疾病患者的遗传和代谢特征提出假说 正在接受抗病毒治疗的失代偿性丙型肝炎肝硬变。具体目标是1)确定是否 脂肪变性和糖尿病的遗传危险因素影响失代偿期丙型肝炎患者的临床恢复 以直接作用抗病毒药物为基础的方案成功治疗后的肝硬变，以及2)确定 胰岛素敏感性的表型差异影响临床恢复。对遗传因素的理解 调解临床改进对临床和转化科学很重要。我们的结果将有助于实现 对肝移植患者进行评估，并引领未来的治疗方法，以改善患者的预后 预后因素差的患者。这项提议的第二个目标是提供一个培训计划， 让邓恩博士获得成为一名独立临床研究员所需的技能和经验。 长期目标是使用患者基因组和表型数据进行患者量身定制的治疗，更准确 特定于患者的预后预测，以及针对人群的最佳疾病预防策略 风险最高。邓恩博士组建了一个多学科指导团队，将监督一个项目，该项目将导致 临床研究和统计遗传学进一步培训的理学硕士学位。他还将收到 科学交流和研究小组管理方面的培训。完成本5年的工作 研究和培训计划将为邓恩博士独立的内科医生职业生涯做准备--科学家和 肝病个体化用药领域的临床研究人员。

Abstract Advances in the treatment of hepatitis C virus (HCV) have, for the first time, created a situation in which patients with very advanced disease can readily achieve virological cure. However, preliminary indications suggest that as many as one third of those patients will continue to progress despite being “cured” of the virus. The factors that will determine the outcome, and thus the best management, of patients with post-viral, advanced liver disease are largely unknown. Chronic HCV infection is associated with insulin resistance and steatosis, which promote fibrosis progression. We postulate that factors associated with fibrosis progression during the active disease are inversely associated with clinical recovery and fibrosis regression after the resolution of the active disease. The central hypothesis of this proposal is that the normalization of insulin resistance and steatosis is central to clinical recovery and fibrosis regression in patients with HCV cirrhosis, and genetic variability in insulin responsiveness and steatosis accounts for the heterogeneous responses after treatment of the primary disease. We will prospectively test our hypothesis by examining the genetic and metabolic characteristics of a large cohort of patients with decompensated HCV cirrhosis undergoing antiviral treatment. The specific aims are 1) to determine if the genetic risk factors for steatosis and diabetes influence clinical recovery in patients with decompensated HCV cirrhosis after successful treatment with a direct-acting antiviral agents based regimen, and 2) to determine if phenotypic differences in insulin sensitivity influence clinical recovery. An understanding of the genetic factors that mediate clinical improvement is important for clinical and translational science. Our results will help target patients for liver transplant evaluation and lead to future therapeutic approaches that improve outcomes for patients with poor prognostic factors. A second goal of this proposal is to provide a training program that will allow Dr. Dunn to attain the skills and experiences necessary to become an independent clinical investigator. The long-term goal is to use patient genomic and phenotypic data for patient-tailored treatment, more accurate patient-specific prognosis prediction, and optimal targeting of disease-prevention strategies to populations at highest risk. Dr. Dunn has assembled a multidisciplinary mentoring team that will oversee a program leading to a Master’s of Science in Clinical Research and further training in statistical genetics. He will also receive training in scientific communication and the management of a research group. Completion of this 5-year research and training plan will prepare Dr. Dunn for an independent career as a Physician-Scientist and Clinical Researcher in the area of personalized medicine for liver disease.