权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Delineating the function of MHC class III genes in antigen presenting myeloid cell contribution to autoimmunity

描述 MHC III 类基因在抗原呈递骨髓细胞对自身免疫的贡献中的功能

基本信息

批准号：
10641866
负责人：
Michael W Lipscomb
金额：
$ 23.25万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2022-06-09 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10641866
关键词：
3-Dimensional Antigen Presentation Antigen-Presenting Cells Autoantigens Autoimmune Autoimmune Diseases Autoimmunity Automobile Driving Biocompatible Materials Biological Assay CRISPR screen Cellular biology Clinical Colitis Coupled Data Dendritic Cells Development Disease Disease Progression Disease susceptibility Environment Equilibrium Evaluation Failure Foundations Frequencies Gene Cluster Genes Genetic Polymorphism Genetic Transcription Genetic Variation Health Immune Immune response Immunity Immunobiology Immunotherapy In Vitro Individual Infiltration Inflammation Inflammatory Inflammatory Response Inflammatory Response Pathway Insulin-Dependent Diabetes Mellitus Intestines Investigation Knowledge MHC Class I Genes Macrophage Measures Modeling Monitor Myeloid Cells Onset of illness Organ Organoids Pathology Pattern Pharmacotherapy Physiological Pilot Projects Play Population Study Predisposition Publishing RNA Interference RNA interference screen Repression Rheumatoid Arthritis Role Series Severity of illness Signal Transduction Spontaneous colitis System Systemic Lupus Erythematosus T cell infiltration T cell response T-Lymphocyte Tissues Variant Work adaptive immune response antigen-specific T cells autoreactive T cell autoreactivity combat design effective therapy follow-up gene function genome-wide genomic locus immunoregulation in vivo innovation insight insulitis mouse model novel novel therapeutics prevent public health relevance repaired response screening success systemic autoimmune disease transcriptomic profiling

项目摘要

SUMMARY The MHC class locus has been associated with several diseases. Notably, genome-wide population studies have identified pivotal polymorphisms within MHC class III (MHC-III) genes that are directly associated with autoimmune diseases, including type 1 diabetes (T1D), intestinal bowel disease (IBD), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), among others. Although less understood, variations in expression patterns of MHC-III genes correlate with disease severity, both dependent and independent from predisposition-related polymorphisms within the MHC class I and II regions. This would suggest that MHC-III genes can govern immunity vs. tolerance in autoimmune settings, with genetic variations potentially increasing susceptibility to disease severity. However, much remains unknown regarding the underpinning mechanistic functions of MHC-III genes in directing autoimmunity. This major gap prevents our understanding of the collective and interconnective roles of these clustered genes in health and disease. Furthermore, this continues to limit clinical success in immune-based therapies largely due to our incomplete knowledge of governing factors driving myeloid cell biology. This is important as failures in the function of antigen presenting myeloid cells, such as dendritic cells (DC) and macrophages, can cause organ-specific and systemic autoimmune diseases. Therefore, it is the long-term objective of these studies to determine the underlying mechanistic role of MHC-III genes in antigen presenting myeloid cells and their contribution to inflammatory diseases. To help resolve the existing knowledge gap within the field, the proposed set of investigations will determine the functional role of MHC-III genes in driving pro-inflammatory responses (Aim 1) and their role in priming autoreactive T cell responses (Aim 2). Extensive preliminary investigations have performed an unbiased high-throughput transcriptomic profiling coupled with RNAi screening to identify key MHC-III genes believed to play key functional roles in macrophages and DC. In Aim 1, studies will intricately evaluate the role of candidate MHC-III genes in macrophages in vitro using a novel 3D organoid. The studies will additionally define the mechanisms of key MHC-III genes in initiating and sustaining inflammation in vivo using both insulitis and colitis autoimmune mouse models. For Aim 2, investigations will describe the pivotal role of MHC-III genes in governing the priming of T cells in vivo. Studies will monitor changes in frequency, infiltration and effector responses of autoantigen-specific T cells in absence of key MHC-III genes within DC subsets to rigorously define their immunoregulatory roles. Collectively, understanding the determinants of MHC-III genes in regulating macrophage and DC biology under autoimmune conditions would have broad implications for effective design of novel immunotherapies.

总结