Genetic Regulation of IgE Glycosylation

IgE 糖基化的遗传调控

基本信息

批准号：
10653875
负责人：
Jeffrey SoRelle
金额：
$ 15.35万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-16 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653875
关键词：
Affect Alleles Allergens Allergic Allergic Disease Allergic Reaction Anaphylaxis Animal Model Antibodies Antigens Asthma B-Lymphocytes Binding Biochemical Bypass CRISPR/Cas technology Cell Count Cell Line Cells Cellular Assay Cellular Immunology Clinical Collection Cytoplasmic Granules Defect Development Diphenhydramine Disease Disease model Economic Burden Eczema Enzymes Ethylnitrosourea Food Hypersensitivity Fructose Functional disorder Future Genes Genetic Genetic Predisposition to Disease Genetic Screening Glycolysis Goals Grant Health Health system Hereditary Disease Histamine Release Human Humor Hypersensitivity IgE Immune Immune system Immunity Impairment In Vitro Institution Investigation Isomerase K-Series Research Career Programs Knock-in Knockout Mice Learning Life Link Lysosomes Mannose Maps Mass Spectrum Analysis Measures Mediating Medicine Meiosis Mentors Metabolic Metabolism Methods Modeling Molecular Biology Mouse Strains Mus Mutagens Mutate Mutation Names Papain Paper Pathway interactions Peptide Hydrolases Peritoneal Phenotype Physicians Physiological Population Process Production Proteins Proteomics Regulation Research Personnel Resistance Resources Role Scientist Secondary to Severities Signal Transduction Structure Supplementation Surface T-Lymphocyte Temperature Testing Translating Writing career cell type clinically relevant conditional knockout crosslink gene discovery genetic testing glycosylation inorganic phosphate insight interest mannose 6 phosphate mast cell meetings mouse model new therapeutic target novel novel therapeutic intervention passive sensitization receptor skills sugar therapeutic target trafficking

项目摘要

Project Summary Allergic diseases including asthma, eczema, and food allergy have increased substantially over the last few decades. These diseases affect almost 5% of the population and having an annual economic burden of over 80 billion dollars. Allergic reactions can be life-threatening. While we have learned much about how an allergic reaction occurs, much remains unknown about how allergies develop. Genetic predisposition is important in developing allergies, but few defined mutations in specific genes are known to cause allergic disease. Recently, we conducted an allergy screen in mutagenized mice to discover genes that regulate production of allergen-specific IgE, which mediates allergic reactions. Among several phenotypes of interest, benadryl is marked by 90% reduced IgE levels and resistance to anaphylaxis with otherwise normal immunity. benadryl was ascribed to a mutation a gene that produces mannose used for glycosylation (adding sugars to proteins), metabolism and targeting proteases to the lysosome. IgE glycosylation is important for its structure and function. Therefore (1), we will determine how the benadryl mutation affects IgE by identifying the cell type responsible for low IgE through a combination of in vitro cell assays and conditional knock-out mouse models. To determine the effect of altered mannose (2), we will examine alterations to IgE glycosylation, stability, and function along with measuring changes to metabolism and lysosomal trafficking. To assess the importance of benadryl in allergic disease (3), we will determine whether benadryl mice are resistant to IgE mediated anaphylaxis and food allergy. Upon successful completion, the findings of this study will reveal a new pathway important for IgE production that would be an appealing therapeutic target. I plan to use these results to launch my career using this mouse strain to understand how altered IgE glycosylation regulates IgE stability, clearance and function. Few other investigators are exploring this topic, which will allow me to study this into the future independently without overlap with my current mentor’s line of scientific investigation. My career goal is to be an independent physician scientist determining the genes that regulate IgE production, which can be clinically translated to genetic tests and potential therapeutic targets. This career development award will help me gain skills in molecular biology, animal models of allergy, cellular immunology, and proteomics. Biannual meetings with my mentoring committee will guide early career milestones including submission of multiple papers. Institutional grant writing resources will be used to successfully compete for an R01 to gain independence.