Targeting CaMK4 in SLE

描述(申请人提供)：系统性红斑狼疮(SLE)是一种病因不明的自身免疫性疾病，以多种T细胞效应器功能障碍为特征。白介素2(IL-2)的产生在SLE患者和狼疮易感小鼠中减少，这有助于疾病的免疫发病机制。这一建议是基于已发表的初步数据，这些数据表明，SLE患者血清中存在的抗CD3/TCR抗体导致钙/钙调蛋白激酶4(CaMK4)从细胞质转位到细胞核，在那里它抑制IL-2的产生。在狼疮易感的MRL.lpr狼疮易感小鼠中，用一种小的药物抑制物抑制或基因缺失CaMK4可抑制自身免疫、系膜细胞增殖和狼疮性肾炎。在更多的数据中，CaMK4似乎参与了调节性T细胞的产生。根据这些数据，我们推测CaMK4通过抑制IL-2的产生和Treg功能参与自身免疫的表达，并通过促进系膜细胞的增殖而参与狼疮性肾炎的发生发展。首先，我们将确定CaMK4转位到SLE T细胞的核，确定它是如何被激活的，以及它是如何影响免疫调节的。其次，我们将确定CaMK4在系膜细胞中的表达是否与狼疮性肾炎的过度增殖和发展独立相关。第三，我们计划使用载有CaMK4抑制剂并标记抗体的纳米凝胶将药物输送到T细胞和系膜细胞。为了进行研究，我们将使用细胞 来自SLE患者和一只新构建的缺乏CaMK4和纳米凝胶技术的MRL.lpr小鼠来研究CaMK4抑制剂。该方案确定了一种新的丝氨酸/苏氨酸蛋白激酶，CaMK4，在调节/失调系膜细胞的免疫反应和增殖中，并建议使用一种新的纳米凝胶递送系统来靶向针对T细胞和系膜细胞的CaMK4的小分子药物抑制剂。这项拟议工作的意义在于，它为系统性红斑狼疮的治疗提供了一个新的靶点，并开发了一种靶向递送的小药物。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an autoimmune disorder of unknown etiology characterized by diverse T cell effector dysfunction. Interleukin-2 (IL-2) production is decreased in patients with SLE and lupus-prone mice and this contributes to the immunopathogenesis of the disease. This proposal is based on published and preliminary data which demonstrate that anti-CD3/TCR antibodies present in the sera of patients with SLE cause translocation of Calcium/calmodulin kinase 4 (CaMK4) from the cytoplasm to the nucleus where it suppresses IL-2 production. In the lupus prone MRL.lpr lupus-prone mouse, pharmacologic inhibition or genetic deletion of CaMK4 with a small drug inhibitor suppresses autoimmunity, mesangial cell proliferation and lupus nephritis. In additional data, CaMK4 appears to be involved in the generation of regulatory T cells. Based on these data we hypothesize that the ser/thr kinase CaMK4 contributes to the expression of autoimmunity by suppressing IL-2 production and Treg function and to the development of lupus nephritis by promoting mesangial cell proliferation. First, we will establish that CaMK4 translocates to the nucleus of SLE T cells, determine how it becomes activated and how it affects immunoregulation. Second, we will establish whether CaMK4 expressed in mesangial cells is independently responsible for excessive proliferation and the development of lupus nephritis. And, third, we plan to use nanolipogels loaded with an inhibitor of CaMK4 and tagged with antibodies to deliver the drug to T and mesangial cells. To carry out the studies we will use cells from patients with SLE and a newly constructed MRL.lpr mouse which lacks CaMK4 and nanolipogel technology to delver the CaMK4 inhibitor. The proposal identifies a new Ser/Thr kinase, CaMK4, in the regulation/dysregulation of the immune response and proliferation of mesangial cells and proposes the use of a novel nanolipogel delivery system to target a small drug inhibitor of CaMK4 to T and mesangial cells. The significance of the proposed work lies with the fact that it presents a novel target for the treatment of SLE and that it develops a targeted delivery of a small drug.