Targeted Ion Channel Downregulation By Nanoparticles: A Novel Therapeutic approa

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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.