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。 银屑病是一种慢性炎症性疾病，影响美国2-3%的人口。这种疾病最常见的局限于皮肤，但也可以涉及肌肉骨骼系统，很少涉及胃肠道和眼睛。自身反应性T细胞似乎是银屑病疾病的发病机制的关键，因为它们的记忆表型和激活的T淋巴细胞诱导银屑病的能力，在移植的非病变皮肤在SCID小鼠-人皮肤异种移植模型。因此，选择性抑制自身反应性记忆T细胞长期以来一直是银屑病新疗法开发的目标。随着电压门控钾通道Kv1.3，我们最近确定了一个令人兴奋的新的分子靶点，允许CCR 7效应记忆T（TEM）细胞的药理学抑制。Kv1.3的表达在CD 4+和CD 8 + TEM细胞中均增加，并且Kv1.3阻断剂已显示出有效地抑制它们的增殖和细胞因子分泌，而不损害原始和中央记忆T细胞的功能。 使用小分子和肽类Kv1.3阻断剂，我们通过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细胞主要是高Kv1.3的TEM细胞，并且Kv1.3阻断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阻断剂PAP-1在口服或局部给药时也有效抑制大鼠变应性接触性皮炎（ACD）的事实，我们现在打算探索Kv1.3在银屑病中的作用。根据本提案的目的-1，我们将使用免疫组织化学、流式细胞术和电生理学研究的组合来确定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Kv1.3高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小鼠模型中的治疗功效。我们将特别研究口服和局部PAP-1治疗是否减少了移植皮肤中治疗前后的网栓长度、单核细胞浸润程度和病变CD 3+、HLA-DR+和Kv1.3+淋巴细胞的数量。本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，这种疾病的特征是片状皮肤，并可能与手，手腕，脚，脚踝，膝盖和脊柱关节炎有关。在这项资助的帮助下，我们将研究一种非常特殊的称为“效应记忆T细胞”的白色血细胞在银屑病中的作用。我们将进一步测试一种通过阻断钾通道Kv1.3靶向“效应记忆T细胞”的新研究药物是否可以治疗移植有人类银屑病皮肤的小鼠的银屑病。我们的研究工作将有助于开发更好的患者护理和治疗牛皮癣和关节炎。

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.