Drug and Viral Induced Thyroiditis and Diabetes

描述(由申请人提供)： 我们的目标是剖析慢性丙型肝炎病毒(HCV)感染患者发生甲状腺炎和糖尿病的潜在机制，以设计新的治疗和预防模式。美国近270万人患有慢性丙型肝炎，导致 每年多达13,000人死亡。此外，在退伍军人中，丙型肝炎病毒感染率明显更高；因此，慢性丙型肝炎病毒是退伍军人医院的一个主要问题。然而，丙型肝炎病毒感染本身及其治疗(IFNA)经常引发甲状腺炎和糖尿病，从而使这些患者的管理复杂化。在之前的资助周期中，我们在剖析丙型肝炎患者发生甲状腺炎和糖尿病的机制方面取得了重大进展。我们证明了丙型肝炎病毒和干扰素通过直接的甲状腺毒性作用和甲状腺炎症易感基因的表观遗传修饰来触发甲状腺炎。此外，我们第一次能够用丙型肝炎病毒感染人类甲状腺细胞。此外，我们最近发现，IFNA还导致胰岛细胞的表观遗传学变化，这表明了一种新的诱导丙型肝炎患者糖尿病的机制(见进展报告)。在目前的提案中，我们将在这些发现的基础上，剖析丙型肝炎病毒和IFNA引发甲状腺炎和糖尿病的机制。我们的假设是，接受IFNA治疗的丙型肝炎病毒感染患者发生甲状腺炎和/或糖尿病，分别是由于甲状腺细胞和胰岛β细胞中的甲状腺炎和糖尿病易感基因的直接表观遗传修饰。我们的具体目标是：特定目标1：我们将在体外测试感染丙型肝炎病毒并暴露于IFNA的人甲状腺细胞中诱导的全基因组表观遗传修饰；我们还将通过创建一个新的四环素可诱导的IFNA在甲状腺中表达的转基因小鼠，在体内评估甲状腺的表观遗传效应。具体目标2：我们将检验这一假设，即丙型肝炎病毒和IFNA通过表观遗传修饰对β细胞具有直接毒性作用，从而导致丙型肝炎病毒感染患者的糖尿病。与加州大学Jason Blackard博士的团队合作，我们将研究人类贝塔细胞系暴露于丙型肝炎病毒蛋白或传染性病毒粒子的表观遗传效应，以及IFNA在人类贝塔细胞中诱导的表观遗传修饰。具体目标3：我们将测试IFNA在除甲状腺和胰腺之外的其他组织中的全身作用，方法是系统地用IFNA治疗小鼠，并检测其对全局甲基化、组蛋白修饰和选定组织(血液、肝脏、脂肪和肌肉)miR表达的影响。综上所述，我们提出的研究将剖析接受IFNA治疗的慢性丙型肝炎患者中导致甲状腺炎和糖尿病的分子机制。慢性丙型肝炎感染是退伍军人的主要健康问题，而甲状腺炎和糖尿病是这些患者常见的并存疾病，严重干扰了慢性丙型肝炎的有效治疗。了解慢性丙型肝炎患者的甲状腺炎和糖尿病的病因将有助于根据这些患者的糖尿病和甲状腺炎的触发机制开发新的治疗模式和预防策略。这些针对丙型肝炎患者的甲状腺炎和糖尿病的新的预防和治疗策略将促进治疗和 退伍军人和非退伍军人慢性丙型肝炎的治疗。

DESCRIPTION (provided by applicant): Our goal is to dissect the mechanisms underlying the development of thyroiditis and diabetes in patients with chronic hepatitis C virus (HCV) infection in order to design new treatment and prevention modalities. Nearly 2.7 million individuals in the US have chronic hepatitis C, resulting in up to 13,000 deaths per year. Moreover, the prevalence of HCV infection is significantly higher among veterans; thus, chronic HCV is a major problem in VA hospitals. However, both HCV infection itself and its therapy (IFNa) frequently trigger thyroiditis and diabetes, thereby complicating the management of these patients. In the previous grant cycle, we made significant progress in dissecting the mechanisms by which thyroiditis and diabetes develop in HCV patients. We demonstrated that HCV and IFNa trigger thyroiditis by direct thyroid toxic effects and through epigenetic modifications in thyroiditis-susceptibility genes. In addition, we were able, for the first time, to infect human thyroid cells with HCV. Moreover, we recently discovered that IFNa also causes epigenetic changes in islet cells, suggesting a new mechanism for inducing diabetes in HCV patients (see Progress Report). In the current proposal, we will build on these findings and dissect the mechanisms by which HCV and IFNa trigger thyroiditis and diabetes. Our hypothesis is that patients with HCV infection treated with IFNa develop thyroiditis and/or diabetes due to direct epigenetic modifications of thyroiditis and diabetes-susceptibility genes in thyroid cells and islet beta cells, respectively. Our specific aims are: Specific Aim 1: we will test in vitro genome-wide epigenetic modifications induced in human thyroid cells infected with HCV and exposed to IFNa; we will also evaluate epigenetic effects in the thyroid in vivo by creating a new transgenic mouse with tetracycline-inducible IFNa expression in the thyroid. Specific Aim 2: we will test the hypothesis that HCV and IFNa have direct toxic effects on beta cells through epigenetic modifications, causing diabetes in HCV-infected patients. In collaboration with Dr. Jason Blackard's group from UC, we will examine the epigenetic effects of exposure of a human beta cell line to HCV viral proteins or infectious virions, as well as the epigenetic modifications induce by IFNa in human beta cells. Specific Aim 3: we will test systemic effects of IFNa in other tissues, in addition to the thyroid and pancreas, by treating mice with IFNa systemically, and examining its effects on global methylation, histone modifications, and miR expression in selected tissues (blood, liver, fat, and muscle). In summary, our proposed studies will dissect the molecular mechanisms causing thyroiditis and diabetes in chronic hepatitis C patients receiving IFNa. Chronic hepatitis C infection is a major health problem for veterans, and thyroiditis and diabetes are common co-morbid conditions in these patients that significantly interfere with effective treatment of chroni HCV. Understanding the etiology of thyroiditis and diabetes in chronic HCV patients will enable the development of novel treatment modalities and prevention strategies based on the mechanisms triggering diabetes and thyroiditis in these patients. These new prevention and treatment strategies for thyroiditis and diabetes in HCV patients will facilitate the treatment and cure of chronic hepatitis C in veterans and non-veterans.