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Calcium channel CACNB1 in T cell function and immunity

钙通道 CACNB1 在 T 细胞功能和免疫中的作用

基本信息

批准号：
9811165
负责人：
STEFAN FESKE
金额：
$ 16.95万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2021-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9811165
关键词：
Adoptive Transfer Affect Antibodies Antibody Affinity Antiviral Agents Apoptosis Autoimmune Diseases Autoimmunity B-Lymphocytes Binding Biological Brain CD4 Positive T Lymphocytes Calcium Calcium Channel Calcium Signaling Cardiac Myocytes Cell membrane Cell physiology Cells Clonal Expansion Colitis Complex Coupling Custom Data Disease Disputes Electric Stimulation Genes Genetic study Goals Growth Guide RNA Heart Helper-Inducer T-Lymphocyte Homeostasis Image Immune Immune response Immunity Immunoglobulin G Immunoglobulin M In Vitro Infection Inflammation Ion Channel Knockout Mice Leukocytes Libraries Light Lymphocyte Function Lymphocytic choriomeningitis virus Measurement Mediating Membrane Methods Movement Mus Mutation Neurons Physiological Play Production Proliferation Marker Proteins Reagent Reporting Research Rheumatoid Arthritis Role Signal Transduction Signaling Molecule Spleen Splenocyte Structure of germinal center of lymph node T cell response T cell therapy T-Cell Activation T-Cell Development T-Cell Receptor T-Lymphocyte Testing Thymus Gland Transgenic Organisms Validation Viral Virus Virus Diseases antiviral immunity cell mediated immune response cytokine experimental study functional genomics in vivo insight knock-down migration mutant neutralizing antibody new therapeutic target novel response retroviral transduction small hairpin RNA small molecule targeted treatment tool trafficking transmission process tumor voltage voltage gated channel

项目摘要

Project Summary The goal of this project is to determine the role of a poorly studied calcium channel subunit in T lymphocytes (T cells) and immune responses. T cells are white blood cells that play a critical role during viral infection by killing virus-infected cells and promoting the production of virus-neutralizing antibodies. The function of T cells depends on calcium channels that form pores in the cell membrane and facilitate the influx of calcium into cells. Inside cells, calcium functions as a signaling molecule that binds to various proteins and promotes the activation of T cells, for instance by regulating the expression of immune modulatory genes. Our lab has extensively studied the function of calcium channels called CRAC channels that are encoded by ORAI and STIM genes. Recent reports suggest that other calcium channels may also mediate calcium influx and T cell function. Among those channels are voltage-gated calcium channels, which are well studied in the heart and brain where they regulate cell function in response to electrical stimulation. The gene studied in this proposal is CACNB1, which encodes one of four known regulatory subunits of voltage-gated calcium channels. CACNB1 is critical for different aspects of channel function including channel trafficking, activation and inactivation. Past research on CACNB1 has focused on excitable cells such as neurons, but CACNB1 is also expressed in T cells, where its role in immune responses remains unknown. Recently, genetic studies of two pore-forming subunits of voltage-gated calcium channels and several regulatory subunits have shown altered function of T cells that lack these channel subunits or express mutant forms. In particular, mutation of the regulatory CACNB2, B3 and B4 genes were reported to affect T cells development in the thymus and homeostasis in the spleen. The role of CACNB1 in T cells has not been investigated yet although it is the most highly expressed of the four regulatory subunits in T cells. Overall, the role of voltage-gated calcium channels in T cells and immune responses remains disputed, which in part is due to their unclear activation mechanism in T cells, which are not electrically excitable. We recently identified CACNB1 in a functional genomics screen in live mice as one of several ion channels that regulates the growth of T cells in response to viral infection of mice. In this application, we propose to further characterize the role of CACNB1 in T cell function and immune responses. Specifically, we will study how deletion of CACNB1 affects calcium signaling, calcium channel function and the ability of T cells to grow, produce immune modulatory cytokines and kill virus-infected cells. Furthermore, we will investigate the consequences of CACNB1 deficiency for immunity to infection by infecting mice whose T cells lack CACNB1 with viruses and analyzing their immune responses. The proposed research will shed new light on the function of CACNB1 and voltage-gated calcium channels in T cells and immune responses. CACNB1 is the most highly and specifically expressed regulatory subunit in T cells and may represent a new drug target for the treatment of autoimmunity and inflammation.