Inhibition of ROCK to reverse T cell dysfunction in SLE

抑制 ROCK 可逆转 SLE 中的 T 细胞功能障碍

• 批准号: 8359139
• 负责人: Jane E Salmon
• 金额: $ 23.69万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359139
• 关键词: Adverse effects; Aftercare; Autoantibodies; Biological Assay; Biological Markers; Biology; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Clinical; Clinical Trials; Combined Modality Therapy; Critical Pathways; Development; Disease; Dose; Effectiveness; Ensure; Exhibits; Functional disorder; Hydroxymethylglutaryl-CoA reductase; Immune; In Vitro; Individual; Inflammatory; Interferon Regulatory Factor 4; Interleukin-17; Intervention; Kidney Diseases; Knowledge; Lupus; Measures; Mediating; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Play; Process; Production; Rho-associated kinase; Role; Series; Signal Pathway; Signal Transduction; Simvastatin; Systemic Lupus Erythematosus; T-Lymphocyte; Therapeutic; Translating; Treatment Protocols; Wild Type Mouse; Work; effective therapy; fasudil; in vitro Assay; inhibitor/antagonist; lupus prone mice; mevalonate; molecular marker; mortality; nervous system disorder; novel; novel therapeutics; outcome forecast; prenylation; response; standard care; therapeutic target; transcription factor

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.

描述（由申请人提供）：尽管SLE患者的预后有了显着改善，但该疾病仍然伴随着明显的发病率和死亡率，许多标准疗法都与显着的副作用有关，表明需要开发有效的治疗疗法。最近的研究最近表明，来自狼疮的小鼠的T细胞表现出增加的Rock2的激活，并且在两个不同的狼疮模型中，抑制这种激酶可以有效地改善疾病，这表明靶向该途径可能是狼疮中广泛的临床效用。鉴于对岩石活性的抑制是负责他汀类药物在本提案中的多效性影响的关键机制之一，我们将探讨以下假设：他汀类药物有效地干扰岩石激活的能力，如果有效地刺激了岩石激活，可以在SLE中发挥有益作用。此外，由于他汀类药物和岩石抑制剂针对该信号级联的两个不同步骤，因此我们将研究与他汀类药物和岩石抑制剂的联合疗法在抑制Rock2方面的结合疗法的可能性，并且在改善狼疮的免疫和临床方面相比，比单一疗法更有效。具体而言，我们将：1）评估辛伐他汀在体外抑制SLE患者T细胞中的Rock2激活，以及是否可以与Fasudil协同作用，岩石抑制剂和2）评估是否可以有效地介入SLE患者的辛伐他汀对SLE患者进行施用。 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他汀类药物治疗仅在抑制Rhoa-Rock途径以及他汀类药物和岩石抑制剂的联合疗法中是否对靶向该途径更有效。鉴于岩石抑制剂已经用于治疗其他疾病的临床用途，并且在这一系列研究的结尾仅显示出最小的副作用，因此可以将这些知识迅速转化为新的治疗方案以治疗SLE。该提案中概述的研究将使新的测定法进行开发，从而可以监测SLE患者的岩石途径，并促进这些药物的临床试验中单个SLE患者的治疗方案的优化，从而允许使用生物标志物作为靶标的“治疗对键入”方法。