Inhibition of ROCK to reverse T cell dysfunction in SLE

描述（由申请人提供）：尽管SLE患者的预后有显著改善，但这种疾病仍然伴随着显著的发病率和死亡率，许多标准治疗与显著的副作用相关，这表明需要开发有效的治疗方法。最近的研究表明，来自狼疮易感小鼠的T细胞表现出增加的ROCK 2活化，并且抑制这种激酶可以有效地改善两种不同的狼疮小鼠模型中的疾病，这表明靶向这种途径可能在狼疮中具有广泛的临床实用性。考虑到ROCK活性的抑制是本提案中他汀类药物多效性作用的关键机制之一，我们将探讨他汀类药物干扰ROCK激活的能力，如果有效利用，可以在SLE中发挥有益作用的假设。此外，由于他汀类药物和ROCK抑制剂靶向该信号级联中的两个不同步骤，我们将研究他汀类药物和ROCK抑制剂的联合治疗在抑制ROCK 2方面协同作用的可能性，并且在改善狼疮的免疫和临床方面比单药治疗更有效。具体而言，我们将：1）评估辛伐他汀是否在体外抑制来自SLE患者的T细胞中的ROCK 2活化，以及其是否可以与ROCK抑制剂法舒地尔协同作用，以及2）评估向SLE患者施用辛伐他汀是否可以有效地干扰ROCK 2活化。 公共卫生相关性：从这些研究中获得的信息将使我们能够确定目前使用的他汀类药物治疗是否仅在抑制RhoA-ROCK通路方面适度有效，以及他汀类药物和ROCK抑制剂的联合治疗是否可以比单一疗法更有效地靶向该通路。考虑到ROCK抑制剂已经在临床上用于治疗其他疾病，并且仅表现出最小的副作用，在这一系列研究结束时，这些知识可以迅速转化为治疗SLE的新治疗方案。本提案中概述的研究将能够开发新的检测方法，这些检测方法将允许监测SLE患者中的ROCK通路，并有助于在这些药物的临床试验中优化个体SLE患者的治疗方案，从而实现以生物标志物为靶点的“治疗靶点”方法。

DESCRIPTION (provided by applicant): Despite remarkable improvements in the prognosis of patients with SLE, this disease is still accompanied by significant morbidity and mortality and many of the standard treatments are associated with significant side effects indicating the need for the development of effective therapies. Recent studies have recently demonstrated that T cells from lupus-prone mice exhibit increased activation of ROCK2 and that inhibiting this kinase can be effective in ameliorating disease in two distinct murine models of lupus suggesting that targeting this pathway may be of broad clinical utility in lupus. Given that inhibition of ROCK activity is one of the key mechanisms responsible for the pleiotropic effects of statins in the present proposal we will explore the hypothesis that the ability of statins to interfere with ROCK activation, if harnessed effectively, can exert beneficial effects in SLE. Furthermore, because statins and ROCK inhibitors target two different steps in this signaling cascade we will investigate the possibility that combination therapy with a statin and a ROCK inhibitor will synergize in inhibiting ROCK2 and be more effective than monotherapy at ameliorating immune and clinical aspects of lupus. Specifically, we will: 1) Assess whether simvastatin inhibits ROCK2 activation in T cells from SLE patients in vitro and whether it can synergize with Fasudil, a ROCK inhibitor and 2) Evaluate whether administration of simvastatin to SLE patients can effectively interfere with ROCK2 activation. PUBLIC HEALTH RELEVANCE: The information obtained from these studies will enable us to determine whether, as presently used, statin therapy is only modestly effective in inhibiting the RhoA-ROCK pathway and whether combination therapy of a statin and a ROCK inhibitor can be more effective in targeting this pathway than monotherapy. Given that ROCK inhibitors are already in clinical use for the treatment of other disorders and have demonstrated only minimal side effects, at the end of this series of studies, this knowledge could be rapidly translated intoa novel therapeutic regimen for the treatment of SLE. The studies outlined in this proposal will enable the development of novel assays that will allow monitoring of the ROCK pathway in SLE patients and facilitate the optimization of treatment regimens for individual SLE patients in clinical trials of these agents, allowing a 'treat-to-target" approach with a biomarker as the target.