Targeting CaMK4 in SLE

SLE 中的靶向 CaMK4

• 批准号: 9247888
• 负责人: George C Tsokos
• 金额: $ 35.94万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247888
• 关键词: Affect; American; Antibodies; Autoimmune Diseases; Autoimmunity; CD3 Antigens; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Cell Death; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Clinical; Collaborations; Cytoplasm; Data; Defect; Development; Disclosure; Disease; Drug Delivery Systems; Effector Cell; Etiology; Functional disorder; Generations; Genetic; Human; Immune; Immune response; Immune system; Interleukin-17; Interleukin-2; Kidney; Lupus; Lupus Nephritis; Molecular; Mus; Organ; Patients; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Production; Proliferating; Publishing; Regulation; Regulatory T-Lymphocyte; Research; System; Systemic Lupus Erythematosus; T-Lymphocyte; Technology; Tissues; Universities; Woman; Work; base; cytotoxic; experimental study; immunoregulation; inhibitor/antagonist; innovation; lupus prone mice; mesangial cell; novel; peripheral blood; public health relevance; response; targeted delivery

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.

描述（由申请人提供）：全身性红斑狼疮（SLE）是一种自身免疫性疾病，其病因不明，其特征是T细胞效应子功能障碍。 SLE和容易发生小鼠的患者的白介素-2（IL-2）产生降低，这有助于该疾病的免疫发病。该提案基于已发表的初步数据，该数据表明，抗cd3/TCR抗体存在于SLE患者的血清中，导致钙/钙调蛋白激酶4（CAMK4）从细胞质到核的钙易位，从而抑制IL-2产生。在容易发生的MRL.LPR狼疮小鼠中，使用小药物抑制剂对CAMK4的药理抑制作用或遗传缺失可抑制自身免疫性，肾小球细胞增殖和狼疮性肾炎。在其他数据中，CAMK4似乎参与了调节性T细胞的产生。基于这些数据，我们假设Ser/Thr激酶CAMK4通过抑制IL-2产生和Treg功能以及通过促进肾小球细胞增殖来抑制IL-2产生和Treg功能以及狼疮肾炎的发展有助于自身免疫性的表达。首先，我们将确定CAMK4易位到SLE T细胞的核，确定其如何激活以及如何影响免疫调节。其次，我们将确定在膜细胞中表达的CAMK4是否对过度增殖和狼疮性肾炎的发育独立负责。第三，我们计划使用带有CAMK4抑制剂并用抗体标记的纳米胶凝物将药物输送到T和肾小球细胞。为了进行研究，我们将使用细胞 来自SLE和新建的MRL.LPR小鼠的患者，该患者缺乏CAMK4和纳米胶质胶质胶质技术来雷管CAMK4抑制剂。该提案在调节/非膜细胞的免疫反应和增殖中确定了一种新的SER/THR激酶CAMK4，并提出了使用新型纳米木凝胶递送系统的使用，以靶向CaMK4的小药物抑制剂对T和膜细胞的小药物抑制剂。提议的工作的重要性在于它为SLE治疗的新目标提供了一个事实，并且它会发展出小药物的目标递送。

项目成果

TARGETING TARGETED TREATMENT FOR IMMUNE AND NON-IMMUNE KIDNEY DISEASES.

• 发表时间: 2019
• 期刊: Transactions of the American Clinical and Climatological Association
• 作者: G. Tsokos;M. Tsokos

KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase IV, promotes generation and function of Foxp3⁺ regulatory T cells in MRL/lpr mice.

• DOI: 10.3109/08916934.2014.915954
• 发表时间: 2014-11
• 期刊: Autoimmunity
• 影响因子: 3.5
• 作者: Koga T;Mizui M;Yoshida N;Otomo K;Lieberman LA;Crispín JC;Tsokos GC
• 通讯作者: Tsokos GC

Calcium/Calmodulin-Dependent Kinase IV Facilitates the Recruitment of Interleukin-17-Producing Cells to Target Organs Through the CCR6/CCL20 Axis in Th17 Cell-Driven Inflammatory Diseases.

• DOI: 10.1002/art.39665
• 发表时间: 2016-08
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Koga T;Otomo K;Mizui M;Yoshida N;Umeda M;Ichinose K;Kawakami A;Tsokos GC
• 通讯作者: Tsokos GC

Amino Acid Metabolism in Lupus.

• DOI: 10.3389/fimmu.2021.623844
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Kono M;Yoshida N;Tsokos GC
• 通讯作者: Tsokos GC

Lupus Nephritis IgG Induction of Calcium/Calmodulin-Dependent Protein Kinase IV Expression in Podocytes and Alteration of Their Function.

• DOI: 10.1002/art.39499
• 发表时间: 2016-04
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Ichinose K;Ushigusa T;Nishino A;Nakashima Y;Suzuki T;Horai Y;Koga T;Kawashiri SY;Iwamoto N;Tamai M;Arima K;Nakamura H;Obata Y;Yamamoto K;Origuchi T;Nishino T;Kawakami A;Tsokos GC
• 通讯作者: Tsokos GC