The REL gene and human autoimmune diseases

REL基因与人类自身免疫性疾病

• 批准号: 8989519
• 负责人: Youhai H Chen
• 金额: $ 20万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8989519
• 关键词: Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Diseases; Binding; Biochemical; Biology; Celiac Disease; Cell Nucleus; Cell physiology; Cells; Colitis; Cytoplasm; DNA; Development; Diabetes Mellitus; Disease; Drug Targeting; Encephalomyelitis; Experimental Autoimmune Encephalomyelitis; FOXP3 gene; Family; Family member; Gene Expression; Genes; Goals; Health; Homologous Protein; Human; Human Activities; Inflammation; Inflammatory; Knockout Mice; Knowledge; Leukocytes; Lymphoid; Mediating; Multiple Sclerosis; Mus; Myelogenous; Nuclear; Pathogenesis; Pathway interactions; Patients; Pharmacologic Substance; Pharmacotherapy; Phenotype; Play; Proteins; Psoriasis; REL gene; Regulatory T-Lymphocyte; Resistance; Rheumatoid Arthritis; Risk; Risk Factors; Role; Severities; Small Interfering RNA; Testing; Time; Ulcerative Colitis; autoimmune arthritis; cell type; clinical practice; cytokine; genome wide association study; member; multiple sclerosis patient; novel; peripheral blood; prevent; primary sclerosing cholangitis; small molecule; theories; tool

 DESCRIPTION (provided by applicant): During the past decade, major advances have been made in our understanding of the pathogenesis of autoimmune diseases. While the etiological factors that trigger the diseases vary, development of autoimmune diseases requires coordinated expression of a unique class of genes called inflammatory genes. Inhibiting the functions of this class of genes is effective for ameliorating autoimmune diseases. However, because autoimmune diseases are mediated by many, if not all, inflammatory genes, inhibiting one or a few of them have only limited efficacies. This application is inspired by two lines of recent discoveries: (I) in humans, several genome-wide association studies independently established that c-Rel is a risk factor for six autoimmune diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS), and (II) in mice, c-Rel deficiency renders them resistant to autoimmune arthritis, encephalomyelitis, colitis, and diabetes. We therefore reasoned that c-Rel is both a risk and pathogenic factor for human autoimmune diseases and that drugs targeting it should be effective for treating the diseases. To test this theory, we have identified two classes of small molecules that specifically inhibit c- Rel function by preventing its binding to DNA. Preliminary studies in mice indicate that these compounds are highly effective in diminishing the severity of ongoing experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. However, most of our knowledge about c-Rel function came from animal studies; the roles of c-Rel in humans are poor understood. Additionally, c-Rel is expressed at high levels by both inflammatory cells and anti-inflammatory regulatory T (Treg) cells; the consequence of pharmaceutical c-Rel inhibition in different cell types is not clear. The goal of this exploratory R21 application is to test the hypothesis that human c-Rel is active in both inflammatory and anti-inflammatory cells and that inhibiting c-Rel in both cell types is required for curing autoimmune diseases.

 描述（由申请人提供）：在过去的十年中，我们对自身免疫性疾病发病机制的理解取得了重大进展。虽然引发疾病的病因因素各不相同，但自身免疫性疾病的发展需要一类称为炎症基因的独特基因的协调表达。抑制这类基因的功能对于改善自身免疫性疾病是有效的。然而，由于自身免疫性疾病是由许多（如果不是全部）炎症基因介导的，因此抑制其中一种或几种炎症基因的疗效有限。本申请的灵感来自两条最近的发现：（I）在人类中，几项全基因组关联研究独立地确定了c-Rel是六种自身免疫性疾病的风险因素，包括类风湿性关节炎（RA）和多发性硬化症（MS），以及（II）在小鼠中，c-Rel缺乏使它们对自身免疫性关节炎、脑脊髓炎、结肠炎和糖尿病具有抗性。因此，我们推断c-Rel是人类自身免疫性疾病的风险和致病因素，靶向它的药物应该对治疗疾病有效。为了验证这一理论，我们已经鉴定了两类通过阻止c-Rel与DNA结合而特异性抑制c-Rel功能的小分子。在小鼠中的初步研究表明，这些化合物在减轻正在进行的实验性自身免疫性脑脊髓炎（EAE）（多发性硬化症的动物模型）的严重程度方面非常有效。然而，我们对c-Rel功能的大部分了解来自动物研究; c-Rel在人类中的作用知之甚少。此外，c-Rel在炎性细胞和抗炎调节性T（Treg）细胞中均以高水平表达;药物c-Rel抑制在不同细胞类型中的结果尚不清楚。这项探索性R21应用的目标是测试人类c-Rel在炎症和抗炎细胞中都有活性的假设，以及抑制两种细胞类型中的c-Rel是治愈自身免疫性疾病所必需的。