The voltage-gated Kv1.3 channel in psoriatic disease: A novel therapeutic target

银屑病疾病中的电压门控 Kv1.3 通道：一个新的治疗靶点

• 批准号: 8318640
• 负责人: SIBA P RAYCHAUDHURI
• 金额: $ 24.26万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-11 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318640
• 关键词: 5-methoxypsoralen; Acute; Affect; Aftercare; Allergic Contact Dermatitis; American; Ankle; Arthritis; Autoimmune Diabetes; Autoimmune Diseases; Bioavailable; CD3 Antigens; CD8B1 gene; Cells; Chronic; Chronic small plaque psoriasis; Cutaneous; Delayed Hypersensitivity; Dependence; Development; Disease; Drug Industry; Electrophysiology (science); Evaluation; Exhibits; Experimental Arthritis; Experimental Autoimmune Encephalomyelitis; Eye; Flow Cytometry; Gastrointestinal tract structure; Goals; Grant; HLA-DR Antigens; Hand; Human; Immunofluorescence Immunologic; Immunohistochemistry; Inflammatory; Inhibitory Concentration 50; Insulin-Dependent Diabetes Mellitus; Investigation; Ion Channel; Joints; Knee; Kv1.3 potassium channel; Length; Lesion; Leukocytes; Lymphocyte; Mediating; Memory; Molecular Target; Mononuclear; Multiple Sclerosis; Mus; Musculoskeletal System; Oral; Organ; Pathogenesis; Pathologic; Patient Care; Patients; Pharmaceutical Preparations; Phenotype; Population; Primates; Pristane; Production; Psoriasis; Psoriatic Arthritis; Rattus; Reporting; Research; Rheumatoid Arthritis; Role; Ruta; Ruta graveolens; SCID Mice; Skin; Synovial Fluid; System; T memory cell; T-Lymphocyte; Tea; Testing; Therapeutic; Tissues; Toxic effect; Transplantation; Treatment Efficacy; United States; Vertebral column; Voltage-Gated Potassium Channel; Work; Wrist; Xenograft Model; alkoxypsoralens; autoreactive T cell; base; cytokine; design; foot; inhibitor/antagonist; mouse model; new therapeutic target; novel; novel therapeutic intervention; prevent; response; skin disorder; skin xenograft; small molecule; terminally differentiated effector memory (TEM) T cells; therapeutic target; voltage

DESCRIPTION (provided by applicant): The Voltage-Gated Kv1.3 Channel In Psoriatic Disease: A Novel Therapeutic Target. Psoriatic disease is a chronic inflammatory disease that affects 2-3% of the population in the United States. The disease is most commonly restricted to the skin but can also involve the musculoskeletal system and rarely the gastrointestinal tract and the eyes. Autoreactive T cells appear to be crucial for the pathogenesis of psoriatic disease because of their memory phenotype and the ability of activated T lymphocytes to induce psoriasis in transplanted nonlesional skin in the SCID mouse-human skin xenograft model. Selective suppression of autoreactive memory T cells has therefore long been an objective for the development of novel therapies for psoriasis. With the voltage-gated potassium channel Kv1.3 we have recently identified an exciting new molecular target that allows for the pharmacological inhibition of CCR7- effector memory T (TEM) cells. Expression of Kv1.3 is increased in both CD4+ and CD8+ TEM cells and Kv1.3 blockers have been shown to potently inhibit their proliferation and cytokine secretion without impairing the function of naove and central memory T cells. Using both small molecule and peptidic Kv1.3 blockers we have further validated Kv1.3 as a potential therapeutic target for TEM cell mediated autoimmune diseases by demonstrating that autoreactive T cells from patients with multiple sclerosis, type-1 diabetes and rheumatoid arthritis are predominantly Kv1.3high TEM cells and that Kv1.3 blockers can treat experimental autoimmune encephalomyelitis, pristane-induced arthritis, and experimental autoimmune diabetes as well as prevent delayed-type hypersensitivity in rats. Based on the fact that the small molecule Kv1.3 blocker PAP-1 also effectively suppresses allergic contact dermatitis (ACD) in rats when administered orally or topically, we now intend to explore the role of Kv1.3 in psoriasis. Under Aim- 1 of this proposal we will determine the functional significance of Kv1.3high effector memory T cells in the pathogenesis of psoriasis and psoriatic arthritis using a combination of immunohistochemistry, flow cytometry and electrophysiology studies. To further substantiate the pathologic role of Kv1.3high TEM cells in psoriatic disease we will then test the therapeutic efficacy of PAP-1 in the psoriasis SCID mouse model under Aim-2. We will specifically investigate whether treatment with oral and topical PAP-1 reduces rete peg lengths, degree of mononuclear cell infiltrates and the number of lesional CD3+, HLA-DR+ and Kv1.3+ lymphocytes pre and post treatment in the transplanted skin. The overall goal of this proposal is to determine whether Kv1.3 blockade constitutes a potential new therapeutic approach to the treatment of psoriasis.

描述（由申请人提供）：银屑病疾病的电压门控KV1.3通道：一种新型的治疗靶标。 银屑病是一种慢性炎症性疾病，影响美国2-3％的人口。该疾病最常限于皮肤，但也可能涉及肌肉骨骼系统，很少胃肠道和眼睛。自动反应性T细胞似乎对于银屑病疾病的发病机理至关重要，因为它们的记忆表型以及活化的T淋巴细胞在SCID小鼠 - 人类皮肤皮肤上移植的非静态皮肤中诱导牛皮癣的能力。因此，选择性抑制自动反应性记忆T细胞长期以来一直是牛皮癣新型疗法发展的目标。使用电压门控钾通道KV1.3，我们最近确定了一个令人兴奋的新分子靶标，该靶标可以对CCR7效应记忆T（TEM）细胞进行药理抑制。在CD4+和CD8+ TEM细胞中，KV1.3的表达均增加，并且已证明KV1.3阻滞剂可有效抑制其增殖和细胞因子分泌，而不会损害NAOVE和中央记忆T细胞的功能。 通过使用小分子和肽KV1.3阻滞剂，我们已经进一步验证了KV1.3，作为TEM细胞介导的自身免疫性疾病的潜在治疗靶点，通过证明来自多发性硬化症，1型糖尿病型和类风湿性关节炎患者的自身反应性T细胞主要治疗KV1.3HHH HIGH TEMIMS CANIMM CANIMM CANMIM CANIMM CANMIM CANMIM CANMIM。脑脊髓炎，丙烷诱发的关节炎和实验性自身免疫性糖尿病，并防止大鼠延迟型超敏反应。基于以下事实：小分子KV1.3阻滞剂PAP-1还有效地抑制了在口服或局部施用大鼠中的大鼠过敏性接触性皮炎（ACD），我们现在打算探索KV1.3在牛皮癣中的作用。在该提案的目标-1下，我们将使用免疫组织化学，流式细胞仪和电生理学研究的组合来确定KV1.3高效应子记忆T细胞在牛皮癣和牛皮癣关节炎的发病机理中的功能意义。为了进一步证实KV1.3高TEM细胞在银屑病疾病中的病理作用，然后我们将在AIM-2下测试牛皮癣SCID小鼠模型中PAP-1的治疗功效。我们将特别研究口服和局部PAP-1的处理是否会减少RETE PEG长度，单核细胞浸润程度以及病变CD3+，HLA-DR+和KV1.3+淋巴细胞的病变数量和在移植皮肤中的治疗前和治疗后的治疗。该提案的总体目标是确定KV1.3阻滞是否构成了牛皮癣治疗的潜在新治疗方法。