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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)是一种破坏性的自身免疫性疾病，影响着500万人全世界。狼疮患者使用皮质类固醇、抗疟疾或抗炎药物治疗疗效有限。FDA批准的Benlysta，一种人类抗B淋巴细胞刺激因子的抗体，下降 SLE患者病情严重，但引起显著副作用(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(TLRs)参与了SLE的发病，并具有靶向性 TLRs是一个很有前途的策略，但TLR信号通路在SLE中的作用尚不完全清楚。几个TLR(TLR2、TLR4、TLR7、TLR9)参与了狼疮，表明以一个TLR为靶点将离开其他TLR启动的信号通路不受影响。这种冗余性决定了需要更全球化的针对常见的促进SLE的TLR通路进行干预。由于IRAK4是一种关键的激酶，即受Pellinos调控，并由参与SLE的大多数TLR启动信号，我们假设IRAK4和IRAK4 Pellino-1/3在狼疮中起关键作用，抑制IRAK4活性将阻断SLE的促进作用小路。这一假说将在以下具体目标中进行检验：1.确定IRAK4的作用 Pellino-1和Pellino-3对狼疮小鼠的影响； 3.测定IRAK4多肽抑制剂对小鼠狼疮的阻断能力。我们期待着揭示如何改变 IRAK4的表达和活性是系统性红斑狼疮的基础，以机械方式定义IRAK4和TLR调节因子的作用 Pellino-1和Pellino-3在狼疮中的表达，并测定IRAK4多肽拮抗剂对小鼠的抑制作用狼疮。这些发现将促进我们对系统性红斑狼疮中IRAK4信号转导的理解，促进药物的设计延缓狼疮的发展，并为SLE患者的翻译研究铺平道路。这样的进步将会对系统性红斑狼疮的基础免疫学和改善美国狼疮患者的公共健康具有关键的重要性。