Document text
Principal Investigator: Anthony Tao
Organization: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $53,974
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Ab-mediated immunity><Ab-mediated protection><Acidity><Acute B-Lymphocytic Leukemia><Address><Adoptive Transfer><Adverse effects><Affect><Anti-CD20 Antibody><Antibodies><Antibody immunity><Antibody protection><Antibody-Producing Cells><Antibody-mediated protection><Antigens><Apoptotic><Attenuated><Autoantibodies><Autoimmune Diseases><Autophagocytosis><B blood cells><B cell><B cell depletion therapy><B cell directed therapy><B cell progenitor acute lymphoblastic leukemia><B cell targeted therapy><B cell therapies><B cell therapy><B cells><B-ALL><B-Cell Acute Lymphocytic Leukemia><B-Cell Activation><B-Cell Acute Lymphoblastic Leukemia><B-Cell Deficiency><B-Cell Development><B-Cell Lymphoblastic Leukemia><B-Cell Subsets><B-Cells><B-Lymphocyte Subsets><B-Lymphocytes><B-cell><B-cell ALL><B-cell precursor acute lymphoblastic leukemia><BLIMP1><Bicarbonates><Biological Agent><Biological Products><Blood Plasma Cell><Blood Precursor Cell><Blood erythrocyte><Bp35><C2B8 Monoclonal Antibody><CD20><COVID-19 virus><COVID19 virus><CRISPR><CRISPR editing screen><CRISPR screen><CRISPR-based screen><CRISPR/Cas system><CRISPR/Cas9 screen><Cardiovascular Diseases><Cell Body><Cell Communication and Signaling><Cell Compartmentation><Cell Compartmentations><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular biology><Class Switching><Class Switchings><Clinical><Clinical Treatment Moab><Clustered Regularly Interspaced Short Palindromic Repeats><Co-Transporters><CoV-2><CoV2><Coupled><Defect><Differentiation in cell culture><Disease><Disorder><Disseminated Sclerosis><Drug Targeting><EAE><Erythrocytes><Erythrocytic><Experimental Allergic Encephalitis><Experimental Allergic Encephalomyelitis><Experimental Autoimmune Encephalitis><Experimental Autoimmune Encephalomyelitis><Genes><Genetic Screening><Grippe><Guide RNA><HCO3><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Humoral Immunities><Hydrogen Carbonates><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immunes><Immunize><Immunodeficiency and Immunosuppression Disorders><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Immunoglobulin Isotype-Switch Recombination><Immunoglobulin Switch Recombination><Immunoglobulin-Producing Cells><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunology procedure><Immunomodulation><Impairment><In Vitro><In vitro cell differentiation><Infection><Influenza><Influenza A><Influenza A virus><Influenza Viruses Type A><Influenzavirus A><Intracellular Communication and Signaling><Ion Channel><Ion Transport><Ionic Channels><Ions><Isotype Switching><Isotype Switchings><Leu-16><Lipid Bilayers><MOG glycoprotein><MS4A1><MS4A1 gene><MS4A2><MabThera><Marrow erythrocyte><Mature B-Cell><Mature B-Lymphocyte><Measures><Mediating><Mediator><Membrane Channels><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Metabolic><Mice><Mice Mammals><MoAb Anti-B1><Modeling><Molecular><Molecular Target><Monoclonal Antibodies><Monoclonal Antibody Anti-B1><Multiple Sclerosis><Murine><Mus><Neurology><Orthomyxovirus Type A><Outcome><Ovine><Ovis><PRDI-BF1><PRDM1><PRDM1 gene><Pathogenesis><Pathologic><Pathway interactions><Peripheral><Physiologic><Physiological><Plasma Cells><Plasmacytes><Play><Population Heterogeneity><Pre-B-Cell Leukemia><Precursor B Lymphoblastic Leukemia><Production><Proliferating><Proteins><RNA Seq><RNA sequencing><RNAseq><Red Blood Cells><Red Cell><Regulation><Rituxan><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Severities><Sheep><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Subcellular Process><Surface Proteins><Switch Recombination><System><Testing><Type A Influenza><Vaccines><Validation><Viral><Viral Activity><Viral Diseases><Viral Function><Viral Physiology><Virus Diseases><Wuhan coronavirus><activated B cells><anti-B1><anti-viral immunity><antibody-based immunity><antibody-mediated immunity><antiviral immunity><attenuate><attenuates><autoimmune antibody><autoimmune condition><autoimmune disorder><autoimmune encephalomyelitis><autoimmunity disease><autophagy><autoreactive antibody><biological signal transduction><biologics><biopharmaceutical><biotherapeutic agent><blood cell progenitor><blood corpuscles><blood progenitor><blood stem cell><blood-forming stem cell><cardiovascular disorder><cell biology><cell type><clustered regularly interspaced short palindromic repeats screen><coronavirus disease 2019 virus><coronavirus disease-19 virus><differentiation in culture><differentiation in vitro><diverse populations><druggable target><extracellular><flu infection><flu serotype><flu strain><flu subtype><flu viral strain><flu virus infection><flu virus strain><forward genetics><functional genomics><gRNA><hCoV19><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><heterogeneous population><host response><humoral immunity deficiency><immune modulation><immune regulation><immune system response><immunogen><immunologic assay><immunologic assay/test><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><in vitro cellular differentiation><in vivo><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza serotype><influenza strain><influenza subtype><influenza viral strain><influenza virus infection><influenza virus strain><insular sclerosis><lipid bilayer membrane><mAbs><mRNA Expression><mammalian genome><monoclonal Abs><mouse model><murine model><myelin oligodendrocyte glycoprotein><nCoV2><neutralizing antibody><new drug class><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug class><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><oligodendrocyte-myelin glycoprotein><pathway><pharmacologic><plasma cell differentiation><plasmocyte><population diversity><reconstitute><reconstitution><response><retroviral transduction><rituximab><self reactive antibody><side effect><small molecule><social role><symporter><tositumomab><transcriptome sequencing><transcriptomic sequencing><transcriptomics><validations><viral infection><virtual><virus infection><virus-induced disease>