The role of ion channels and transporters in B cell function

离子通道和转运蛋白在 B 细胞功能中的作用

基本信息

批准号：
10620690
负责人：
Anthony Tao
金额：
$ 5.27万
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：
2022
资助国家：
美国
起止时间：
2022-07-17 至 2025-07-16
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620690
关键词：
2019-nCoV Acidity Address Adoptive Transfer Adverse effects Affect Antibodies Antibody-Producing Cells Antibody-mediated protection Antigens Apoptotic Attenuated Autoantibodies Autoimmune Diseases Autophagocytosis B cell therapy B-Cell Activation B-Cell Acute Lymphoblastic Leukemia B-Cell Development B-Lymphocyte Subsets B-Lymphocytes Bicarbonates Biological Products CRISPR screen Cardiovascular Diseases Cell Compartmentation Cell physiology Cells Cellular biology Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coupled Defect Disease Drug Targeting Erythrocytes Experimental Autoimmune Encephalomyelitis Genes Genetic Screening Guide RNA Hematopoietic stem cells Humoral Immunities Immune Immune System Diseases Immune response Immunize Immunoglobulin Class Switching Immunoglobulin Switch Recombination Immunology procedure Impairment In Vitro Infection Influenza Influenza A virus Ion Channel Ion Transport Ions Lipid Bilayers MS4A1 gene Mature B-Lymphocyte Measures Mediating Mediator Membrane Proteins Metabolic Modeling Molecular Molecular Target Monoclonal Antibodies Multiple Sclerosis Mus Neurology Outcome PRDM1 gene Pathogenesis Pathologic Pathway interactions Peripheral Physiological Plasma Cells Play Population Heterogeneity Production Proliferating Proteins Regulation Role Severities Sheep Signal Pathway Signal Transduction Specificity System Testing Vaccines Validation Viral Viral Physiology Virus Diseases antiviral immunity cell type druggable target extracellular forward genetics functional genomics humoral immunity deficiency immunoregulation in vivo influenza infection influenza virus strain mRNA Expression mammalian genome mouse model neutralizing antibody new therapeutic target novel novel drug class oligodendrocyte-myelin glycoprotein pharmacologic plasma cell differentiation reconstitution response retroviral transduction rituximab side effect small molecule symporter tositumomab transcriptome sequencing transcriptomics virtual

项目摘要

PROJECT SUMMARY/ABSTRACT B cells are a central player in the humoral immune response, which is elicited by differentiated, antibody- producing B cell-types known as plasma cells (PCs). During viral infections such as influenza or SARS-CoV2, PCs produce antibodies that neutralize viral activity. Furthermore, PCs have been implicated in the pathogenesis of many autoimmune diseases, including multiple sclerosis (MS). Thus, the capacity to modulate B cell function, notably PC differentiation and activity, has broad clinical implications. The leading therapy for specific regulation of B cell function is a monoclonal antibody targeting CD20, leading to brash depletion of virtually all B cell subsets and resulting in various side effects. Thus, there is a clinical need for molecular targets that affect B cell function in more refined and precise manners. Ion channels and transporters (ICTs) mediate the flux of ions across the lipid bilayer, which can further regulate intracellular signaling. ICTs are desirable clinical targets because 1) many are surface proteins accessible to biologics and 2) multiple small-molecule ICT modulators have already been developed. Unfortunately, though substantive evidence exists that different ICTs can contribute to different aspects of B function, this intersection remains poorly investigated. To address this gap, I will leverage transcriptomic analyses and functional genomics, coupled with experimental validations. Based on an RNA-seq and a CRISPR screen, I came across SLC4A7, a Na+/HCO3- co-transporter known to regulate intracellular pH. Deletion of SLC4A7 in B cells selectively impaired PC differentiation in vitro and in vivo. In Aim 1, I will further characterize how SLC4A7 affects PC differentiation signaling pathways, intracellular pH, and the autophagy pathway. In Aim 2, I will determine how deletion of SLC4A7 in B cells affects the immune response against influenza infection as well as the pathogenesis of a murine model for MS. Overall, this project will elucidate novel mechanisms by which intracellular pH regulates PC differentiation and reveal a novel target (SLC4A7) with which B cell function can be modulated, especially in the context of MS.

项目概要/摘要 B 细胞是体液免疫反应的核心参与者，体液免疫反应是由分化的抗体引发的。产生称为浆细胞 (PC) 的 B 细胞类型。在流感或 SARS-CoV2 等病毒感染期间， PC 产生中和病毒活性的抗体。此外，PC 与发病机制有关许多自身免疫性疾病，包括多发性硬化症（MS）。因此，调节 B 细胞功能的能力，尤其是 PC 分化和活性，具有广泛的临床意义。特定调节的领先疗法 B 细胞功能的主要障碍是一种针对 CD20 的单克隆抗体，可导致几乎所有 B 细胞亚群的快速耗竭并导致各种副作用。因此，临床需要影响 B 细胞功能的分子靶点以更精致、更精确的方式。离子通道和转运蛋白 (ICT) 介导跨脂质双层的离子通量，这可以进一步调节细胞内信号传导。 ICT 是理想的临床靶标，因为 1) 许多是可接近的表面蛋白生物制剂和2）多种小分子ICT调节剂已经开发出来。不幸的是，虽然大量证据表明，不同的 ICT 可以为 B 功能的不同方面做出贡献，这种交叉点仍然没有得到很好的调查。为了解决这一差距，我将利用转录组分析和功能分析基因组学，加上实验验证。基于 RNA 测序和 CRISPR 筛选，我发现 SLC4A7，一种 Na+/HCO3- 协同转运蛋白，已知可调节细胞内 pH 值。选择性删除 B 细胞中的 SLC4A7 体外和体内 PC 分化受损。在目标 1 中，我将进一步描述 SLC4A7 对 PC 的影响分化信号通路、细胞内 pH 值和自噬通路。在目标 2 中，我将确定如何 B 细胞中 SLC4A7 的缺失会影响针对流感感染的免疫反应以及 MS 小鼠模型的发病机制。总的来说，该项目将阐明新的机制细胞内 pH 调节 PC 分化并揭示 B 细胞功能的新靶点 (SLC4A7) 可以进行调节，尤其是在 MS 的情况下。