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（由适用提供）：全身性红斑狼疮（SLE）是一种严重的自身免疫性疾病，影响了全球500万人。用皮质类固醇，抗疟药或抗炎药治疗SLB患者的效率有限。 FDA批准的Benlysta是针对B-淋巴细胞刺激剂的人类单克隆抗体，改善了SLE患者的疾病严重程度，但非裔美国人患者对治疗没有反应。此外，Benlysta引起了重大副作用，例如严重的感染，恶心，腹泻和发烧。这是迫切需要为狼疮制定新的治疗策略。积累的证据支持Toll样受体（TLR）参与SLE，而靶向TLR是一个有前途的策略。几个TLR（TLR2，TLR4，TLR7-9）参与了SLE，表明针对一个TLR会留下其他TLR引发的信号通路。这种冗余决定了对热干预的常见TLR信号通路的更全局靶向。由于IRAK4是一种关键的激酶，它启动了SLE中实施的所有TLR的信号传导，因此我们假设IRAK4活动的增加是狼疮的关键决定者，而IRAK4活动的衰减将减轻狼疮的TLR途径，从而提供IRAK4 ADAPTER功能的保护，同时可以保护Irapter andapter antapter ant antimiCiCripialimicrobiCripimiCiCrobiCripialiCrobiCripiCrobiCripirObiCriCripiCRObiCROBICAICROBICAICRIAMICRIAMICICICRIACICAICAICICRIACE。该假设将在以下特定目的中进行检验：1。定义狼疮易蛋白小鼠SLE进展过程中的IRAK4表达和活性；和2。工程师和测试IRAK4的肽抑制剂，可阻止狼疮易发的小鼠SLE的能力。我们预计，通过将IRAK4激酶活性在机械上定义了IRAK4表达和活性是否是通过将IRAK4激酶活性小鼠与狼疮pronefc¿r2b - /-yaa小鼠进行机械定义的作用的基础，并确定了新的irak4 decoy肽拮抗剂的效用。预计该项目将提供原则上的结果，以促进我们对SLE中IRAK4信号的理解，并为未来的RO1授予生成概念框架，以系统地分析IRAK4表达和活动在SLE中的作用。它将促进小分子组件的计算机辅助设计以抑制IRAK4，并为SLE患者的未来翻译研究铺平道路。这些进步对于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。