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

基本信息

批准号：
8334424
负责人：
LAURA CONFORTI
金额：
$ 17.33万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-17 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8334424
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

项目摘要

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.

描述（由申请人提供）：全身性红斑狼疮（SLE）是一种慢性自身免疫性疾病，主要影响育儿的妇女，这些患者的较高风险较高，死于心血管事件。炎症和早产性动脉粥样硬化在SLE和动脉粥样硬化血管疾病的心血管并发症中起重要作用。现在已经很好地确定，效应记忆T淋巴细胞高度参与动脉粥样硬化，并且由于其功能异常，它们在SLE患者中构成了更大的问题。具体而言，SLE T细胞显示出对抗原表现的夸张反应。因此，纠正SLE中的免疫缺陷至关重要。本提案的目的是在SLE中设计新的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，但对膜相关离子事件的异常的考虑非常有限，这些异常可能影响CA2+信号传导，基因表达和这些细胞中的功能。 KV1.3通道对于适当的T细胞激活至关重要，因为它们调节Ca2+流入。实际上，对这些通道的抑制作用抑制了SLE中的Ca2+反应和T细胞增殖，这使KV1.3成为免疫抑制的有趣靶标。我们在这里提出通过选择性递送KV1.3 siRNAS在SLE记忆T细胞中下调KV1.3的表达。具体而言，我们将设计多价治疗纳米颗粒，以将KV1.3 siRNA靶向递送到记忆T淋巴细胞，并在SLE中建立其免疫抑制功效。这些研究可能会导致在SLE和动脉粥样硬化领域中应用新的治疗方法。