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.

全身性红斑狼疮（SLE）是一种毁灭性的自身免疫性疾病，影响500万人全世界。用皮质类固醇，抗疟药或抗炎药治疗狼疮患者的患者有限的功效。 FDA批准的Benlysta是一种针对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，但会引起重大副作用（感染，恶心，腹泻，发烧）和在非裔美国人中无效。因此，迫切需要制定新的治疗策略狼疮。积累的证据表明，Toll样受体（TLR）参与SLE，而靶向 TLR是一个有前途的策略，但是TLR信号通路在SLE中的作用尚不完全理解。狼疮中有几个TLR（TLR2，TLR4，TLR7，TLR9）参与其他TLR不受影响的信号通路。这种冗余决定了需要更全球的靶向促进SLE的TLR途径进行干预。因为irak4是一个关键的激酶由佩里诺斯（Pellinos Pellino-1/3在狼疮中起关键作用，抑制IRAK4活动将阻止SLE促进途径。该假设将在以下特定目的中进行检验：1。定义IRAK4的作用狼疮发育中的表达和活性； 2。确定佩里诺-1和佩里诺-3对鼠狼疮的影响；和3。确定IRAK4肽抑制剂阻断鼠狼疮的能力。我们希望揭示如何改变 irak4表达和活动是SLE的基础，以机械地定义IRAK4和TLR调节剂狼疮中的Pellino-1和Pellino-3，并确定IRAK4肽拮抗剂抑制鼠的效用狼疮。这些发现将提高我们对SLE中IRAK4信号的理解，促进药物的设计减弱狼疮的发育，并为SLE患者的翻译研究铺平道路。这样的进步会对于SLE的基本免疫学和改善美国狼疮患者的公共卫生至关重要