Drug and Viral Induced Thyroiditis and Diabetes

药物和病毒引起的甲状腺炎和糖尿病

• 批准号: 8442424
• 负责人: YARON TOMER
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442424
• 关键词: ATP8A2 gene; Beta Cell; Blood; Cell Line; Cells; Cessation of life; Chronic Hepatitis C; Collaborations; Development; Diabetes Mellitus; Disease; Epigenetic Process; Etiology; Fatty acid glycerol esters; Gene Expression Regulation; Genes; Goals; Grant; Health; Hepatitis C; Hepatitis C virus; Hospitals; Human; In Vitro; Individual; Infection; Interferon-alpha; Islet Cell; Lead; Liver; Mediating; Methylation; Modality; Modeling; Modification; Molecular; Mus; Muscle; Pancreas; Patients; Pharmaceutical Preparations; Prevalence; Prevention; Prevention strategy; Production; Progress Reports; Protein Binding; Proteins; RNA chemical synthesis; Role; Structure of beta Cell of islet; Susceptibility Gene; Testing; Tetracyclines; Thyroid Gland; Thyroiditis; Time; Tissues; Toxic effect; Transgenic Mice; Veterans; Viral; Viral Proteins; Virion; Virus; base; cytokine; design; effective therapy; genome-wide; histone modification; in vitro testing; in vivo; islet; mouse model; novel; public health relevance; response; treatment strategy; viral RNA

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.

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）感染患者甲状腺炎和糖尿病发生的机制，以设计新的治疗和预防方法。美国有近270万人患有慢性丙型肝炎， 每年有13,000人死亡此外，HCV感染的患病率显着较高的退伍军人，因此，慢性HCV是VA医院的一个主要问题。然而，HCV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。在上一个资助周期中，我们在剖析HCV患者甲状腺炎和糖尿病发生的机制方面取得了重大进展。 我们证明了HCV和IFNa通过直接的甲状腺毒性作用和甲状腺炎易感基因的表观遗传修饰引发甲状腺炎。此外，我们首次能够用HCV感染人类甲状腺细胞。此外，我们最近发现IFNa还引起胰岛细胞的表观遗传变化，这表明HCV患者诱导糖尿病的新机制（见进展报告）。在目前的提案中，我们将建立在这些发现的基础上，并剖析HCV和IFNa触发甲状腺炎和糖尿病的机制。 我们的假设是，用IFNa治疗的HCV感染患者由于甲状腺炎和糖尿病易感基因分别在甲状腺细胞和胰岛β细胞中的直接表观遗传修饰而发生甲状腺炎和/或糖尿病。 我们的具体目标是：具体目标1：我们将在体外检测感染HCV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;我们还将通过创建甲状腺中具有四环素诱导的IFNa表达的新转基因小鼠来评估体内甲状腺中的表观遗传效应。 具体目标二：我们将检验HCV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HCV感染患者发生糖尿病的假设。与加州大学的Jason Blackard博士的小组合作，我们将研究人类β细胞系暴露于HCV病毒蛋白或感染性病毒粒子的表观遗传效应，以及IFNa在人类β细胞中诱导的表观遗传修饰。 具体目标3：我们将通过用IFN α全身性治疗小鼠，并检查其对选定组织（血液、肝脏、脂肪和肌肉）中的整体甲基化、组蛋白修饰和miR表达的影响，来测试IFN α在除甲状腺和胰腺之外的其他组织中的全身性作用。 总之，我们提出的研究将剖析在接受IFNa治疗的慢性丙型肝炎患者中引起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一个主要健康问题，甲状腺炎和糖尿病是这些患者常见的并发症，严重干扰慢性丙型肝炎的有效治疗。了解慢性丙型肝炎患者甲状腺炎和糖尿病的病因，将使新的治疗方式和预防策略的基础上触发这些患者的糖尿病和甲状腺炎的机制的发展。这些针对HCV患者甲状腺炎和糖尿病的新的预防和治疗策略将促进HCV患者的治疗， 治疗慢性丙型肝炎的退伍军人和非退伍军人。