IRAK4 and Systemic Lupus Erythematosus

系统性红斑狼疮（SLE）是一种毁灭性的自身免疫性疾病，影响500万人 国际吧用皮质类固醇、抗疟药或抗炎药治疗狼疮患者， 有限的功效。FDA批准的Benlysta是一种针对B淋巴细胞刺激因子的人抗体， SLE患者的疾病严重程度，但引起显著的副作用（感染、恶心、腹泻、发热）， 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（TLR）参与SLE，靶向 TLR是一种很有前途的策略，但TLR信号通路在SLE中的作用尚不完全清楚。 几种TLR（TLR 2、TLR 4、TLR 7、TLR 9）参与狼疮，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一个更全球化的 靶向常见的SLE促进TLR途径进行干预。由于IRAK 4是一种重要的激酶， 由Pellinos调节并通过参与SLE的大多数TLR启动信号传导，我们假设IRAK 4和 Pellino-1/3在狼疮中起关键作用，抑制IRAK 4活性将阻断SLE促进 途径。该假设将在以下具体目标中进行检验：1.定义IRAK 4的角色 在狼疮发展中的表达和活性; 2.确定Pellino-1和Pellino-3对小鼠狼疮的影响; 和3.确定IRAK 4肽抑制剂阻断鼠狼疮的能力。我们希望能揭示 IRAK 4表达和活性是SLE的基础，以机械地定义IRAK 4和TLR调节剂的作用 Pellino-1和Pellino-3在狼疮中的作用，并确定IRAK 4肽拮抗剂用于抑制鼠 狼疮这些发现将促进我们对SLE中IRAK 4信号传导的理解，促进药物设计， 减轻狼疮的发展，并为SLE患者的转化研究铺平道路。这种进步将 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。

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.