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

摘要 丙型肝炎病毒（HCV）治疗的进展首次创造了一种情况， 患有非常晚期疾病的患者可以容易地实现病毒学治愈。然而，初步迹象表明， 这表明，这些患者中有多达三分之一的人尽管被“治愈”了病毒，但仍将继续进展。 将决定结果的因素，从而最好的管理，患者的病毒感染后， 晚期肝病在很大程度上是未知的。慢性HCV感染与胰岛素抵抗有关， 脂肪变性，其促进纤维化进展。我们假设与纤维化进展相关的因素 在活动性疾病期间，与临床恢复和纤维化消退呈负相关， 活动性疾病的消退。这个建议的中心假设是胰岛素的正常化 耐药性和脂肪变性是HCV患者临床恢复和纤维化消退的核心 肝硬化，胰岛素反应性和脂肪变性的遗传变异性解释了 原发病治疗后的异质反应。我们将前瞻性地测试 通过检查一个大型队列患者的遗传和代谢特征， 正在接受抗病毒治疗的失代偿性HCV肝硬化。具体目标是：1）确定 脂肪变性和糖尿病的遗传危险因素影响失代偿HCV患者的临床恢复 肝硬化后，成功治疗与直接作用的抗病毒药物为基础的方案，和2），以确定是否 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 对临床和转化科学来说是很重要的。我们的研究结果将有助于 患者进行肝移植评估，并导致未来的治疗方法， 预后不良的患者。该提案的第二个目标是提供一个培训方案， 使Dunn博士获得成为独立临床研究者所需的技能和经验。 长期目标是利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 患者特异性预后预测，以及疾病预防策略的最佳针对性， 最高风险邓恩博士组建了一个多学科的指导小组，将监督一个项目， 临床研究科学硕士学位和统计遗传学的进一步培训。他还将收到 科学交流和研究小组管理方面的培训。完成这5年 研究和培训计划将为Dunn博士作为一名物理学家-科学家的独立职业生涯做好准备， 肝病个性化医疗领域的临床研究员。

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.