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

描述(由申请人提供)：银屑病中的电压门控Kv1.3通道：一种新的治疗靶点。牛皮癣是一种慢性炎症性疾病，影响美国2%-3%的人口。这种疾病通常局限于皮肤，但也可能累及肌肉骨骼系统，很少涉及胃肠道和眼睛。在SCID小鼠-人皮肤异种移植模型中，自身反应性T细胞似乎在银屑病的发病机制中起关键作用，因为它们的记忆表型和激活的T淋巴细胞在移植的非皮损皮肤中诱导银屑病的能力。因此，选择性抑制自身反应性T细胞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，它允许对CCR7效应记忆T(TEM)细胞进行药理抑制。Kv1.3在CD4+和CD8+的TEM细胞中的表达均增加，Kv1.3阻滞剂可有效地抑制其增殖和细胞因子的分泌，而不损害NAOVE和中央记忆T细胞的功能。通过使用小分子和多肽Kv1.3阻断剂，我们进一步验证了Kv1.3是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Kv1.3高TM细胞，Kv1.3阻滞剂可以治疗实验性自身免疫性脑脊髓炎、Pristane诱导的关节炎和实验性自身免疫性糖尿病，并可以预防大鼠的迟发型超敏反应。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变态反应性接触性皮炎(ACD)的事实，我们现在打算探索Kv1.3在银屑病中的作用。根据这项建议的目标-1，我们将结合免疫组织化学、流式细胞术和电生理学研究，确定Kv1.3高效记忆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Kv1.3高透射电子显微镜细胞在银屑病中的病理作用，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。我们将专门研究口服和外用PAP-1治疗是否会减少移植皮肤治疗前后的网状连接长度、单个核细胞浸润程度以及皮损CD3+、HLA-DR+和Kv1.3+淋巴细胞的数量。这项提案的总体目标是确定Kv1.3阻断是否构成治疗牛皮癣的潜在新疗法。 与公共卫生相关：近2%的美国人患有牛皮癣，这种疾病的特征是皮肤剥落，可能与手、腕、脚、脚踝、膝盖和脊柱的关节关节炎有关。在这笔赠款的帮助下，我们将研究一种非常特殊的白血球类型，即“效应记忆T细胞”在银屑病中的作用。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牛皮癣皮肤的小鼠的牛皮癣。这种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的患者护理和治疗。

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.