Targeted Ion Channel Downregulation By Nanoparticles: A Novel Therapeutic approa

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种慢性自身免疫性疾病，主要影响育龄妇女，这些患者死于心血管事件的风险较高。炎症和过早动脉粥样硬化在SLE心血管并发症和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，它们在SLE患者中构成更大的问题，因为它们的功能异常。具体来说，SLE T细胞对抗原呈递表现出夸张的反应。因此，纠正SLE患者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。虽然已经在SLE T细胞中发现了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措施，但对膜相关离子事件异常的考虑非常有限，这些离子事件可以影响这些细胞中的Ca2+信号、基因表达和功能。Kv1.3通道调节Ca2+内流，对T细胞的正常激活至关重要。事实上，这些通道的抑制抑制了SLE中的Ca2+反应和T细胞增殖，使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来下调SLE记忆T细胞中Kv1.3的表达。具体来说，我们将设计用于靶向递送Kv1.3 siRNA到记忆T淋巴细胞的多价治疗纳米颗粒，并将确定其在SLE中的免疫抑制功效。这些研究可能会导致新的治疗方法在SLE和动脉粥样硬化领域的应用。

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.