IRAK4 and Systemic Lupus Erythematosus

IRAK4 和系统性红斑狼疮

基本信息

批准号：
9920669
负责人：
Anthony T Vella
金额：
$ 39.88万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920669
关键词：
3-Dimensional Address Adrenal Cortex Hormones Affect African African American American Anti-Inflammatory Agents Antibodies Antimalarials Antinuclear Antibodies Apoptosis Attenuated Autoimmune Diseases B-Lymphocytes Biological Cells DNA Deoxyribonucleases Development Diarrhea Disease Drug Design Engineering Excision FDA approved Fever Genetic Models Health Hepatitis B Virus Human Human Herpesvirus 4 IRAK1 gene IRAK3 gene IRAK4 gene ITGAM gene Immune Immunology Impairment Infection Interferon-alpha Intervention Lead Leukocytes Light Link Liver Lupus Mediating Messenger RNA Migraine Mus Mutation Myeloid Cells Natural Immunity Nausea Nephritis Osteoporosis Pathogenesis Pathway interactions Patients Peptides Peripheral Blood Mononuclear Cell Peritoneal Permeability Pharmaceutical Preparations Pharmacology Phosphotransferases Play Pristane Public Health RNA Reporting Retina Role Serum Severity of illness Signal Pathway Signal Transduction Single Nucleotide Polymorphism Systemic Lupus Erythematosus TALL-1 protein TLR2 gene TLR4 gene TLR7 gene TNF gene Testing The Sun Toll-Like Receptor Pathway Toll-like receptors Transgenic Mice Tumor Necrosis Factor Ligand Superfamily Member 6 United States National Institutes of Health Work autoreactive B cell belimumab cytokine effective therapy improved in vivo inhibitor/antagonist lupus prone mice microbial mortality novel therapeutic intervention novel therapeutics recruit response side effect trafficking translational study ubiquitin-protein ligase

项目摘要

Systemic lupus erythematosus (SLE) is a devastating autoimmune disease that affects 5 million people worldwide. Treatment of lupus patients with corticosteroids, antimalarial, or anti-inflammatory drugs have limited efficacy. FDA-approved Benlysta, a human antibody against B-lymphocyte stimulator, decreased disease severity in SLE patients, but caused significant side effects (infections, nausea, diarrhea, fever) and was ineffective in African Americans. Thus, there is an urgent need to develop new therapeutic strategies for lupus. Accumulating evidence demonstrates the involvement of Toll-like receptors (TLRs) in SLE, and targeting TLRs is a promising strategy, but the role of TLR signaling pathways in SLE is incompletely understood. Several TLRs (TLR2, TLR4, TLR7, TLR9) are involved in lupus, indicating that targeting one TLR would leave signaling pathways initiated by other TLRs unaffected. This redundancy dictates the need for a more global targeting of common SLE-promoting TLR pathways for intervention. Since IRAK4 is a critical kinase that is regulated by Pellinos and initiates signaling by most TLRs involved in SLE, we hypothesize that IRAK4 and Pellino-1/3 play a critical role in lupus and that inhibition of IRAK4 activity will block SLE-promoting pathways. The hypothesis will be tested in the following Specific Aims: 1. Define the role of IRAK4 expression and activity in lupus development; 2. Identify the impact of Pellino-1 and Pellino-3 on murine lupus; and 3. Determine the ability of IRAK4 peptide inhibitors to block murine lupus. We expect to reveal how altered IRAK4 expression and activity underlies SLE, to mechanistically define the role of IRAK4 and TLR regulators Pellino-1 and Pellino-3 in lupus, and determine the utility of IRAK4 peptide antagonists for inhibiting murine lupus. These findings will advance our understanding of IRAK4 signaling in SLE, facilitate design of drugs to attenuate lupus development, and pave the way for translational studies in SLE patients. Such advances would be of key importance for basic immunology of SLE, and for improving public health of lupus patients in the U.S.

系统性红斑狼疮 (SLE) 是一种毁灭性的自身免疫性疾病，影响着 500 万人全世界。使用皮质类固醇、抗疟药或抗炎药治疗狼疮患者功效有限。 FDA 批准的 Benlysta（一种抗 B 淋巴细胞刺激剂的人类抗体）降低了 SLE 患者的疾病严重程度，但引起了显着的副作用（感染、恶心、腹泻、发烧）和对非裔美国人无效。因此，迫切需要开发新的治疗策略狼疮。越来越多的证据表明 Toll 样受体 (TLR) 参与 SLE，并且靶向 TLR 是一种很有前景的策略，但 TLR 信号通路在 SLE 中的作用尚不完全清楚。狼疮涉及多种 TLR（TLR2、TLR4、TLR7、TLR9），表明针对一种 TLR 会导致狼疮其他 TLR 启动的信号通路不受影响。这种冗余决定了需要一个更加全球化的针对常见的 SLE 促进 TLR 途径进行干预。由于 IRAK4 是一种关键激酶，由于 IRAK4 受 Pellinos 调节，并通过参与 SLE 的大多数 TLR 启动信号传导，我们假设 IRAK4 和 Pellino-1/3 在狼疮中发挥关键作用，抑制 IRAK4 活性将阻止 SLE 促进途径。该假设将在以下具体目标中得到检验： 1. 定义 IRAK4 的作用狼疮发展中的表达和活动； 2. 确定Pellino-1和Pellino-3对小鼠狼疮的影响； 3.确定IRAK4肽抑制剂阻断小鼠狼疮的能力。我们希望揭示如何改变 IRAK4 表达和活性是 SLE 的基础，从机制上定义 IRAK4 和 TLR 调节因子的作用 Pellino-1 和 Pellino-3 在狼疮中的作用，并确定 IRAK4 肽拮抗剂在抑制小鼠中的效用狼疮。这些发现将增进我们对 SLE 中 IRAK4 信号传导的理解，促进药物设计减缓狼疮的发展，并为 SLE 患者的转化研究铺平道路。这些进步将对于 SLE 的基础免疫学以及改善美国狼疮患者的公共健康至关重要