Inhibition of ROCK to reverse T cell dysfunction in SLE

描述(申请人提供)：尽管系统性红斑狼疮患者的预后有了显著的改善，但这种疾病仍然伴随着严重的发病率和死亡率，许多标准的治疗方法都与显著的副作用有关，这表明需要开发有效的治疗方法。最近的研究表明，狼疮易感小鼠的T细胞表现出ROCK2的激活增加，抑制该激酶可以有效地改善两种不同的狼疮小鼠模型的疾病，提示靶向这一途径可能在狼疮中具有广泛的临床实用价值。鉴于抑制岩石活性是他汀类药物多效性的关键机制之一，我们将探讨这样的假设，即他汀类药物干扰岩石激活的能力，如果有效利用，可以在SLE中发挥有益的作用。此外，由于他汀类药物和ROCK抑制剂针对这一信号级联中的两个不同步骤，我们将研究他汀类药物和ROCK抑制剂联合治疗在抑制ROCK2方面协同作用的可能性，并在改善狼疮的免疫和临床方面比单一治疗更有效。具体地说，我们将：1)评估辛伐他汀是否在体外抑制SLE患者T细胞中ROCK2的激活，以及它是否能与ROCK抑制剂法舒地尔协同作用；2)评估给SLE患者使用辛伐他汀是否可以有效地干扰ROCK2的激活。

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.