Targeted Ion Channel Downregulation By Nanoparticles: A Novel Therapeutic approa

纳米颗粒靶向离子通道下调：一种新的治疗方法

• 批准号: 8242217
• 负责人: LAURA CONFORTI
• 金额: $ 22.14万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-17 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242217
• 关键词: Acute; Adverse effects; Affect; Animal Model; Antibodies; Antigen Presentation; Atherosclerosis; Autoimmune Diseases; Cardiovascular Diseases; Cardiovascular system; Cell physiology; Cells; Chronic; Defect; Development; Disease; Double-Stranded RNA; Down-Regulation; Engineering; Event; Gene Expression; Genes; Human; Hyperactive behavior; Immune; Immune System and Related Disorders; Immunosuppression; Immunosuppressive Agents; Infection; Inflammation; Intervention; Ion Channel; Lead; Left; Membrane; Membrane Proteins; Multiple Sclerosis; Nanotechnology; Patients; Play; Potassium; Potassium Channel; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Small Interfering RNA; Systemic Lupus Erythematosus; T memory cell; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic Intervention; Therapeutic immunosuppression; Woman; atherogenesis; child bearing; chronic autoimmune disease; design; gene function; high risk; immune function; interest; knock-down; nanoparticle; novel; novel therapeutic intervention; novel therapeutics; premature atherosclerosis; response; targeted delivery; terminally differentiated effector memory (TEM) T cells

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.

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，这些患者因心血管事件而年轻死亡的风险较高。炎症和过早动脉粥样硬化在系统性红斑狼疮的心血管并发症以及动脉粥样硬化性血管疾病中发挥着重要作用。现在已经明确，效应记忆T淋巴细胞高度参与动脉粥样硬化形成，并且由于其功能异常，它们在SLE患者中构成了更大的问题。具体来说，SLE T 细胞对抗原呈递表现出过度反应。因此，纠正 SLE 中的免疫缺陷至关重要。本提案的目的是设计 SLE 的新治疗性免疫抑制干预措施。尽管已经在 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，但对可能影响这些细胞中 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 通道对于 T 细胞的正常激活至关重要，因为它们调节 Ca2+ 流入。事实上，抑制这些通道会抑制 SLE 中的 Ca2+ 反应和 T 细胞增殖，从而使 Kv1.3 成为免疫抑制的有趣靶点。我们在此建议通过选择性递送 Kv1.3 siRNA 来下调 SLE 记忆 T 细胞中 Kv1.3 的表达。具体来说，我们将设计多价治疗纳米颗粒，将 Kv1.3 siRNA 靶向递送至记忆 T 淋巴细胞，并确定其在 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系统性红斑狼疮和动脉粥样硬化领域的应用。 公众健康相关性：自身免疫性疾病系统性红斑狼疮 (SLE) 患者的 T 淋巴细胞异常活跃，其中一部分 T 细胞导致这些患者出现心血管并发症。阻断这些 T 细胞中高表达的钾通道会降低其功能。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。