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IRAK4 and systemic lupus erythematosus

IRAK4 与系统性红斑狼疮

基本信息

批准号：
8509341
负责人：
ANDREI E MEDVEDEV
金额：
$ 18.68万
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：
2013
资助国家：
美国
起止时间：
2013-08-19 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8509341
关键词：
Address Adrenal Cortex Hormones Adverse effects Affect African American Anemia Anti-Inflammatory Agents Anti-inflammatory Antibodies Antibody Formation Antigen-Antibody Complex Antimalarials Antimicrobial Resistance Apoptosis Apoptotic Arthritis Autoantibodies Autoimmune Diseases Autoimmunity B-Lymphocytes Biological Cell surface Cells Chromatin Computer-Aided Design DNA Dendritic Cells Development Diagnostic Diarrhea Disease Double-Stranded RNA Endocytosis Endosomes Engineering Enzymes Etiology Exanthema FDA approved Fever Future Glomerulonephritis Grant HMGB1 Protein Health Human IRAK4 gene Immune Immune system Immunology Infection Inflammation Inflammatory Interferons Lead Left Leukopenia Link Lupus Mediating Messenger RNA Molecular Monitor Mus Mutation National Institute of Allergy and Infectious Disease Natural Immunity Nausea Neurologic Neutrophil Activation Nuclear Nucleic Acids Organ Patients Peptides Pharmaceutical Preparations Phosphotransferases Predisposition Process Production Public Health RNA Receptor Signaling Receptors, Antigen, B-Cell Reporting Research Role Science Severity of illness Signal Pathway Signal Transduction Systemic Lupus Erythematosus T-Lymphocyte TALL-1 protein TLR1 gene TLR2 gene TLR3 gene TLR4 gene TLR7 gene Testing Therapeutic Intervention Thrombocytopenia To autoantigen Toll-Like Receptor Pathway Toll-like receptors Translational Research Vasculitis Viral Work attenuation autoreactive B cell autoreactive T cell belimumab cellular engineering cytokine human monoclonal antibodies improved inhibitor/antagonist insight lupus prone mice macrophage male microbial monocyte mouse model novel therapeutic intervention novel therapeutics prevent protective effect public health relevance sensor small molecule systemic autoimmune disease trafficking treatment strategy uptake

项目摘要

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a severe autoimmune disease that affects 5 million people worldwide. Treatment of SLB patients with corticosteroids, antimalarial, or anti-inflammatory drugs have limited efficacy. FDA-approved Benlysta, a human monoclonal antibody against B-lymphocyte stimulator, decreased disease severity in SLE patients, but African American patients did not respond to treatment. Furthermore, Benlysta caused significant side effects such as severe infections, nausea, diarrhea, and fever. Thus, there is an urgent need to develop new therapeutic strategies for lupus. Accumulating evidence supports the involvement of Toll-like receptors (TLRs) in SLE, and targeting TLRs is a promising strategy. Several TLRs (TLR2, TLR4, TLR7-9) are involved in SLE, 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 TLR signaling pathways for therapeutic intervention. Since IRAK4 is a critical kinase that initiates signaling by all TLRs implicated in SLE, we hypothesize that increased IRAK4 activity is the critical determinant of lupus and that attenuation of IRAK4 activity will mitigate lupus-promoting TLR pathways, providing protection against SLE, while preserving IRAK4 adapter functions that contribute to antimicrobial resistance. The hypothesis will be tested in the following Specific Aims to: 1. Define IRAK4 expression and activity during progression of SLE in lupus-prone mice; and 2. Engineer and test peptide inhibitors of IRAK4 for their ability to block SLE in lupus-prone mice. We expect to define if altered IRAK4 expression and activity underlies development of SLE in mice, mechanistically define the role of IRAK4 kinase activity by crossing IRAK4 kinase-inactive mice with lupus-prone Fc¿R2b-/- Yaa mice, and determine the utility of new IRAK4 decoy peptide antagonists for inhibiting lupus in mice. This project is expected to provide proof-of-principle results to advance our understanding of IRAK4 signaling in SLE, and to generate the conceptual framework for a future RO1 grant to systematically analyze the role of IRAK4 expression and activity in SLE. It will facilitate computer-assisted design of small molecular components to inhibit IRAK4, and will pave the way for future translational research in SLE patients. These advances would be of key importance for basic immunology of SLE, and for improving public health of lupus patients in the U.S.

描述（由申请人提供）：系统性红斑狼疮 (SLE) 是一种严重的自身免疫性疾病，影响全球 500 万人。使用皮质类固醇、抗疟药或抗炎药治疗 SLB 患者的疗效有限。 FDA 批准的 Benlysta 是一种抗 B 淋巴细胞刺激剂的人单克隆抗体，可降低 SLE 患者的疾病严重程度，但非洲裔美国患者对治疗没有反应。此外，Benlysta 还引起严重的副作用，如严重感染、恶心、腹泻和发烧。因此，迫切需要开发新的狼疮治疗策略。越来越多的证据支持 Toll 样受体 (TLR) 参与 SLE，而靶向 TLR 是一种有前景的策略。 SLE 涉及多种 TLR（TLR2、TLR4、TLR7-9），这表明针对一种 TLR 不会影响其他 TLR 启动的信号通路。这种冗余表明需要对常见 TLR 信号通路进行更全面的靶向治疗干预。由于 IRAK4 是一种关键激酶，可启动与 SLE 相关的所有 TLR 信号传导，因此我们假设 IRAK4 活性增加是狼疮的关键决定因素，而 IRAK4 活性的减弱将减轻狼疮促进的 TLR 通路，提供针对 SLE 的保护，同时保留有助于抗菌素耐药性的 IRAK4 接头功能。该假设将在以下具体目标中得到检验： 1. 确定易患狼疮的小鼠在 SLE 进展过程中的 IRAK4 表达和活性； 2. 设计并测试 IRAK4 肽抑制剂在易患狼疮的小鼠中阻断 SLE 的能力。我们希望确定 IRAK4 表达和活性的改变是否是小鼠 SLE 发展的基础，通过将 IRAK4 激酶失活小鼠与易患狼疮的 Fc¿R2b-/- Yaa 小鼠杂交，从机制上确定 IRAK4 激酶活性的作用，并确定新的 IRAK4 诱饵肽拮抗剂在抑制小鼠狼疮方面的效用。该项目预计将提供原理验证结果，以增进我们对 SLE 中 IRAK4 信号传导的理解，并为未来 RO1 拨款生成概念框架，以系统分析 IRAK4 表达和活性在 SLE 中的作用。它将促进计算机辅助设计抑制IRAK4的小分子成分，并为未来SLE患者的转化研究铺平道路。这些进展对于系统性红斑狼疮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。