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

基本信息

批准号：
8048520
负责人：
SIBA P RAYCHAUDHURI
金额：
$ 13.82万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-11 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8048520
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: Nearly 2% of Americans have psoriasis, a disease that is characterized by flakey skin and that can be associated with arthritis of joints of the hands, wrist, feet, ankle, knee, and spine. With the help of this grant we will investigate the role of a very specific type of white blood cells called "effector memory T cells" in psoriasis. We will further test whether a new investigative drug, which targets "effector memory T cells" by blocking the potassium channel Kv1.3, can treat psoriasis in mice transplanted with human psoriatic skin. Our research work will help to develop better patient care and treatment of psoriasis and arthritis.

描述（由申请人提供）：银屑病中的电压门控 Kv1.3 通道：一种新型治疗靶点。银屑病是一种慢性炎症性疾病，影响美国 2-3% 的人口。该疾病最常见限于皮肤，但也可累及肌肉骨骼系统，很少累及胃肠道和眼睛。自身反应性 T 细胞似乎对银屑病的发病机制至关重要，因为它们具有记忆表型，并且活化的 T 淋巴细胞能够在 SCID 小鼠-人皮肤异种移植模型中诱导移植的非病变皮肤中诱发银屑病。因此，选择性抑制自身反应性记忆 T 细胞长期以来一直是开发银屑病新疗法的目标。通过电压门控钾通道 Kv1.3，我们最近发现了一个令人兴奋的新分子靶点，它可以对 CCR7 效应记忆 T (TEM) 细胞进行药理学抑制。 CD4+ 和 CD8+ TEM 细胞中 Kv1.3 的表达均增加，Kv1.3 阻滞剂已被证明可有效抑制其增殖和细胞因子分泌，而不损害幼稚 T 细胞和中枢记忆 T 细胞的功能。使用小分子和肽 Kv1.3 阻滞剂，我们进一步验证了 Kv1.3 作为 TEM 细胞介导的自身免疫性疾病的潜在治疗靶点，证明来自多发性硬化症、1 型糖尿病和类风湿性关节炎患者的自身反应性 T 细胞主要是 Kv1 .3high TEM 细胞和 Kv1.3 阻滞剂可以治疗实验性自身免疫性脑脊髓炎、降植烷诱导的关节炎和实验性自身免疫性糖尿病以及预防大鼠迟发型超敏反应。基于小分子 Kv1.3 阻滞剂 PAP-1 在口服或局部给药时也能有效抑制大鼠过敏性接触性皮炎 (ACD)，我们现在打算探讨 Kv1.3 在银屑病中的作用。根据本提案的目标 1，我们将结合免疫组织化学、流式细胞术和电生理学研究来确定 Kv1.3 高效应记忆 T 细胞在银屑病和银屑病关节炎发病机制中的功能意义。为了进一步证实 Kv1.3high TEM 细胞在银屑病疾病中的病理作用，我们将在 Aim-2 下测试 PAP-1 在银屑病 SCID 小鼠模型中的治疗效果。我们将具体研究口服和局部 PAP-1 治疗是否会减少移植皮肤治疗前后的网状钉长度、单核细胞浸润程度以及病变 CD3+、HLA-DR+ 和 Kv1.3+ 淋巴细胞的数量。该提案的总体目标是确定 Kv1.3 阻断是否构成治疗银屑病的潜在新治疗方法。公共卫生相关性：近 2% 的美国人患有牛皮癣，这种疾病的特征是皮肤鳞片状，可能与手、腕、脚、踝、膝和脊柱关节关节炎有关。在这笔资助的帮助下，我们将研究一种非常特殊的白细胞类型，称为“效应记忆 T 细胞”在牛皮癣中的作用。我们将进一步测试一种新的研究药物是否可以治疗移植了人类银屑病皮肤的小鼠的银屑病，该药物通过阻断钾通道 Kv1.3 来靶向“效应记忆 T 细胞”。我们的研究工作将有助于开发更好的牛皮癣和关节炎患者护理和治疗方法。