Targeting CaMK4 in SLE

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种病因不明的自身免疫性疾病，其特征是多种T细胞效应器功能障碍。白细胞介素-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。该建议基于已发表的和初步的数据，这些数据表明SLE患者血清中存在的抗CD 3/TCR抗体导致钙/钙调蛋白激酶4（CaMK 4）从细胞质易位到细胞核，在细胞核中其抑制IL-2的产生。在狼疮易感MRL.lpr狼疮易感小鼠中，用小药物抑制剂对CaMK 4进行药理学抑制或基因缺失可抑制自身免疫、系膜细胞增殖和狼疮性肾炎。在其他数据中，CaMK 4似乎参与调节性T细胞的产生。基于这些数据，我们推测，Ser/Thr激酶CaMK 4有助于通过抑制IL-2的产生和调节性T细胞功能的自身免疫的表达和狼疮性肾炎的发展，通过促进系膜细胞增殖。首先，我们将确定CaMK 4易位到SLE T细胞的细胞核，确定它如何被激活以及它如何影响免疫调节。其次，我们将确定系膜细胞中表达的CaMK 4是否独立地负责过度增殖和狼疮性肾炎的发展。第三，我们计划使用装载有CaMK 4抑制剂并标记有抗体的纳米脂质体凝胶将药物递送到T细胞和系膜细胞。为了进行研究，我们将使用细胞 来自SLE患者和新构建的MRL.lpr小鼠，其缺乏CaMK 4和纳米脂质体凝胶技术以获得CaMK 4抑制剂。该提案确定了一种新的Ser/Thr激酶CaMK 4在免疫应答和系膜细胞增殖的调节/失调中的作用，并提出使用新型纳米脂质体凝胶递送系统将CaMK 4的小药物抑制剂靶向T细胞和系膜细胞。所提出的工作的意义在于，它为SLE的治疗提供了一个新的靶点，并且它开发了一种小药物的靶向递送。

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.