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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：
8722427
负责人：
ANDREI E MEDVEDEV
金额：
$ 23.86万
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 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8722427
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。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是一种针对B淋巴细胞刺激因子的人单克隆抗体，可降低SLE患者的疾病严重程度，但非裔美国人患者对治疗无反应。此外，Benlysta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，靶向TLR是一种有前途的策略。多种TLR（TLR 2、TLR 4、TLR 7 - 9）参与了SLE，这表明靶向一种TLR将使其他TLR启动的信号通路不受影响。这种冗余决定了需要更全面地靶向常见TLR信号传导途径以进行治疗干预。由于IRAK 4是一种关键激酶，可通过SLE中涉及的所有TLR启动信号传导，因此我们假设IRAK 4活性增加是狼疮的关键决定因素，并且IRAK 4活性的减弱将减轻促进狼疮的TLR途径，提供针对SLE的保护，同时保留有助于抗菌素耐药性的IRAK 4衔接子功能。该假设将在以下具体目标中进行检验：1.定义狼疮易感小鼠中SLE进展期间IRAK4的表达和活性;和2.工程和测试IRAK 4的肽抑制剂在狼疮易感小鼠中阻断SLE的能力。我们希望确定IRAK 4表达和活性的改变是否是小鼠SLE发生的基础，通过将IRAK 4激酶失活的小鼠与狼疮易感的Fc <$R2b-/-Yaa小鼠杂交，从机制上确定IRAK 4激酶活性的作用，并确定新的IRAK 4诱饵肽拮抗剂在抑制小鼠狼疮中的效用。该项目预计将提供原理验证结果，以促进我们对SLE中IRAK4信号传导的理解，并为未来的RO1资助产生概念框架，以系统地分析IRAK4表达和活性在SLE中的作用。这将有助于计算机辅助设计抑制IRAK4的小分子组分，并为SLE患者的未来转化研究铺平道路。这些进展对于SLE的基础免疫学和改善美国狼疮患者的公共健康至关重要。