Targeted Ion Channel Downregulation By Nanoparticles: A Novel Therapeutic approa

描述（由申请方提供）：系统性红斑狼疮（SLE）是一种慢性自身免疫性疾病，主要影响育龄期女性，这些患者因心血管事件而早逝的风险较高。炎症和过早动脉粥样硬化在SLE的心血管并发症以及动脉粥样硬化性血管疾病中起重要作用。现在已经确定效应记忆T淋巴细胞高度参与动脉粥样硬化的形成，并且它们在SLE患者中构成更大的问题，因为它们的功能异常。具体而言，SLE T细胞显示出对抗原呈递的过度反应。因此，纠正SLE中的免疫缺陷至关重要。本提案的目的是设计新的治疗性免疫抑制干预SLE。尽管在SLE T细胞中已经鉴定出几种信号分子的缺陷，并且已经考虑了针对它们的治疗干预，但是对可以影响这些细胞中的Ca2+信号传导、基因表达和功能的膜相关离子事件的异常的考虑非常有限。Kv1.3通道对T细胞的正常活化是必不可少的，因为它们调节Ca2+内流。事实上，这些通道的抑制抑制了SLE中的Ca 2+反应和T细胞增殖，使得Kv1.3成为免疫抑制的有趣靶点。我们在此提出通过选择性递送Kv1.3 siRNA下调SLE记忆T细胞中Kv1.3的表达。具体来说，我们将设计多价治疗性纳米颗粒，用于将Kv1.3 siRNA靶向递送至记忆T淋巴细胞，并且我们将确定其在SLE中的免疫抑制功效。这些研究可能导致新的治疗方法在SLE和动脉粥样硬化领域的应用。 公共卫生相关性：自身免疫性疾病系统性红斑狼疮（SLE）患者的T淋巴细胞是过度活跃的，并且T细胞亚群有助于这些患者中发生的心血管并发症。在这些T细胞中高度表达的钾通道的阻断可以降低它们的功能。我们建议选择性地阻断这些T细胞中钾通道的表达，作为SLE的一种新疗法。

DESCRIPTION (provided by applicant): Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that predominantly affects women in their childbearing years and these patients are at higher risk of dying young from cardiovascular events. Inflammation and premature atherosclerosis play an important role in the cardiovascular complications of SLE as well as atherosclerotic vascular disease. It is now well established that effector memory T lymphocytes are highly involved in atherogenesis and they constitute an even bigger problem in SLE patients because their function is abnormal. Specifically, SLE T cells show an exaggerated response to antigen presentation. Thus correcting immune defects in SLE is of primary importance. The objective of the present proposal is to design new therapeutic immunosuppressive interventions in SLE. Although defects in several signaling molecules have been identified in SLE T cells and therapeutic interventions targeting them have been considered, very limited consideration has been given to the abnormalities in membrane-associated ionic events that can affect Ca2+ signaling, gene expression and function in these cells. Kv1.3 channels are essential for proper T cell activation as they regulate Ca2+ influx. Indeed, inhibition of these channels suppresses the Ca2+ response and T cell proliferation in SLE making Kv1.3 an interesting target for immunosuppression. We are herein proposing downregulating Kv1.3 expression in SLE memory T cells by selective delivery of Kv1.3 siRNAs. Specifically we will engineer multivalent therapeutic nanoparticles for the targeted delivery of Kv1.3 siRNA to memory T lymphocytes and we will establish their immunosuppressive efficacy in SLE. These studies could lead to the application of new therapeutic approaches in SLE and in the atherosclerosis field in general. PUBLIC HEALTH RELEVANCE: T lymphocytes in patients with the autoimmune disease Systemic Lupus Erythematosus (SLE) are hyperactive and a subset of T cells contributes to the cardiovascular complications that occur in these patients. Blockade of potassium channels, highly expressed in these T cells, can decrease their function. We propose to block the expression of potassium channels selectively in these T cells as a novel therapy in SLE.