PKCtheta-CD28 interaction: A novel drug target for autoimmunity and inflammation

PKCtheta-CD28 相互作用：自身免疫和炎症的新型药物靶点

• 批准号: 8527431
• 负责人: Elizabeth Yan Zhang
• 金额: $ 5.01万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8527431
• 关键词: Address; Allergic Disease; American; Antigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Biological; Bone Marrow; CD28 gene; Cell Surface Receptors; Cells; Chronic; Colitis; Communicable Diseases; Complex; Crohn' s disease; Data; Development; Diagnosis; Disease; Disease model; Dissection; Dominant-Negative Mutation; Drug Targeting; Effector Cell; Enzymes; Family member; Immune System Diseases; Immune response; Immune system; Immunity; Immunosuppression; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Insulin-Dependent Diabetes Mellitus; Knowledge; Laboratories; Lead; Mediating; Mentors; Mission; Modeling; Molecular; Multiple Sclerosis; Mus; National Institute of Allergy and Infectious Disease; National Institute of Diabetes and Digestive and Kidney Diseases; Play; Population; Protein Kinase C; Proteins; Recruitment Activity; Regulatory T-Lymphocyte; Research Support; Rheumatoid Arthritis; Role; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Transgenic Mice; Virus; Work; allograft rejection; base; design; differentiation retarding activity; immunological synapse; in vivo; inhibitor/antagonist; leukemia; mutant; novel; novel strategies; novel therapeutics; prevent; public health relevance; receptor; response; small molecule; tool

DESCRIPTION (provided by applicant): Approximately 50 million Americans suffer from ~100 known autoimmune diseases (e.g., type I diabetes, Crohn's disease, and rheumatoid arthritis). The proposed studies focus on the impact of a novel TCR-induced interaction between protein kinase C-theta (PKC?) and CD28 on different aspects of immune responses and its implication for treating autoimmune and inflammatory diseases. PKC? is a Ca2+-independent PKC family member that is most abundantly expressed in T cells, and its critical role in conventional T cell activation and survival has been well documented. In vivo studies revealed the selective role of PKC? in different types of immunity. In particular, a recent study showed that in sharp contrast to T effector (Teff) cells, PKC? is excluded from the immunological synapse (IS) of induced regulatory T (iTreg) cells and, moreover, it inhibits their suppressive function. These findings point to the high promise of PKC? as a selective drug target for immunosuppression of T cell-mediated autoimmunity and inflammation. My preliminary data demonstrated that blocking the PKC?-CD28 association by different strategies promoted the differentiation and suppressive function of Treg cells. Here, I will test the hypothesis that blockade of the PKC?-CD28 interaction inhibits the differentiation and activity of pathogenic T cells and promotes the functin of Treg cells, thereby achieving a beneficial synergetic effect against T cell-mediated autoimmune and inflammatory responses. I will use two novel and highly specific complementary tools, i.e., i) blockade of the inducible PKC?-CD28 interaction by a dominant negative PKC? V3-based mutant; and ii) small molecule allosteric compounds generated by our collaborators that I found to inhibit this interaction. In Aim 1, I will analyze the effect of thes strategies on Teff and Treg differentiation and function in vitro, and in Aim 2, I will evaluate th impact of blocking the PKC?-CD28 interaction on an experimental disease model of chronic colitis in mice. The results of this project will reveal the effects of sequestering PKC? from CD28 and the IS on Treg and Teff differentiation and function and uncover a promising novel approach for treating T cell-mediated experimental inflammatory disease, i.e., Th17-mediated colitis. Collectively, this study is likely to pave the way for the development of new, highly selective therapeutic strategies to treat T cell-mediated autoimmunity and inflammation. This project fits seamlessly with the NIAID mission to conduct and support research to study the causes of allergic, immunologic, and infectious diseases, and to develop better means of preventing, diagnosing, and treating these illnesses. Meanwhile, this project also has close relevance to the mission of the NIDDK as it will study the effects of blocking the PKC?-CD28 interaction on an experimental chronic colitis model.

描述（由申请人提供）：大约 5000 万美国人患有约 100 种已知的自身免疫性疾病（例如 I 型糖尿病、克罗恩病和类风湿性关节炎）。拟议的研究重点关注蛋白激酶 C-theta (PKC?) 和 CD28 之间新型 TCR 诱导的相互作用对免疫反应不同方面的影响及其对治疗自身免疫和炎症疾病的影响。 PKC？是 Ca2+ 独立的 PKC 家族成员，在 T 细胞中表达最丰富，其在传统 T 细胞激活和存活中的关键作用已得到充分证明。体内研究揭示了 PKC 的选择性作用？在不同类型的免疫中。特别是，最近的一项研究表明，与效应 T (Teff) 细胞形成鲜明对比的是，PKC？被排除在诱导性调节性 T (iTreg) 细胞的免疫突触 (IS) 之外，此外，它还会抑制其抑制功能。这些发现表明了 PKC 的巨大前景？作为 T 细胞介导的自身免疫和炎症的免疫抑制的选择性药物靶点。我的初步数据表明，通过不同策略阻断PKC？-CD28关联促进了Treg细胞的分化和抑制功能。在这里，我将检验以下假设：阻断 PKC?-CD28 相互作用会抑制致病性 T 细胞的分化和活性，并促进 Treg 细胞的功能，从而实现对抗 T 细胞介导的自身免疫和炎症反应的有益协同效应。我将使用两种新颖且高度特异性的互补工具，即 i) 通过显性负性 PKC? 阻断可诱导的 PKC?-CD28 相互作用。基于V3的突变体； ii）我们的合作者产生的小分子变构化合物，我发现它们可以抑制这种相互作用。在目标 1 中，我将分析这些策略对 Teff 和 Treg 体外分化和功能的影响，在目标 2 中，我将评估阻断 PKC?-CD28 相互作用对小鼠慢性结肠炎实验疾病模型的影响。这个项目的结果将揭示隔离PKC的效果？从 CD28 以及 IS 对 Treg 和 Teff 分化和功能的影响，并揭示了一种治疗 T 细胞介导的实验性炎症疾病（即 Th17 介导的结肠炎）的有前途的新方法。总的来说，这项研究可能为开发新的、高度选择性的治疗 T 细胞介导的自身免疫和炎症的治疗策略铺平道路。该项目与 NIAID 的使命无缝契合，即开展和支持研究过敏、免疫和传染病的原因，并开发更好的方法来预防、诊断和治疗这些疾病。同时，该项目也与 NIDDK 的使命密切相关，因为它将研究阻断 PKC?-CD28 相互作用对实验性慢性结肠炎模型的影响。