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Genetic studies linking LSP1 function in T cells to Inflammatory Bowel Disease

T 细胞中 LSP1 功能与炎症性肠病相关的遗传学研究

基本信息

批准号：
10636526
负责人：
BENJAMIN JOACHIM SCHMIEDEL
金额：
$ 40.26万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10636526
关键词：
Address Affect Apoptosis Arthritis Autoimmune Diseases Automobile Driving Binding Biological Assay Biological Sciences CD4 Positive T Lymphocytes CRISPR interference Cell physiology Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Colitis Collaborations Colonic inflammation Crohn&apos s disease DNA Sequence Databases Delayed Hypersensitivity Disease Disease Progression Enhancers F-actin-binding proteins Gene Expression Genes Genetic Genetic Polymorphism Genetic study Human Immune Immunology Impairment Infiltration Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inherited Knowledge Leukocytes Link Luciferases Mediating Modeling Molecular Morbidity - disease rate Mus Outcome Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Play Production Proliferating Proteins Quantitative Trait Loci RNA Interference Regulation Reporter Reporting Rest Risk Role Science Signal Pathway Small Interfering RNA T cell therapy T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Testing Translating Ulcerative Colitis Untranslated RNA Variant Work causal variant cell motility cell type chromatin immunoprecipitation cytokine cytotoxicity disorder risk epigenomics genetic association genetic variant genome wide association study improved insight loss of function mortality mouse model murine colitis new therapeutic target overexpression phase 3 study prevent programs promoter response restraint risk variant therapeutic target transcription factor tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Inflammatory bowel diseases (IBD) cause substantial mortality and morbidity. Current treatments that block pathological inflammatory responses have improved clinical outcomes in some patients but they are not highly effective in modifying disease progression or preventing relapses. Hence, there is a large unmet need to develop novel therapeutic targets. Genome-wide association studies (GWAS) offer an unbiased approach to identify therapeutic targets in relevant immune cell types such as CD4+ T cells that play key roles in IBD pathogenesis. Because T cells are quiescent in the absence of extrinsic stimulation, it is not possible to fully examine the effects of disease-risk variants on functionally relevant effector genes under resting conditions. To identify IBD-risk genes in activated CD4+ T cells, we performed the first large-scale single-cell eQTL study on activated CD4+ T cells. We found that reduced expression of Leukocyte-specific protein 1 (LSP1), specifically in activated CD4+ T-cell subsets such as TH1 and TH17 cells, was associated with the risk of IBD. In this R01 proposal, we will investigate how reduced levels of LSP1 influences the differentiation and function of CD4+ T cells to drive disease pathogenesis, and will test the hypothesis that LSP1 plays a key role in restraining the re-programming of CD4+ T cells into a more pathogenic cell state in IBD patients. In Aim 1, we will determine the functional IBD-risk variants that reduce LSP1 expression in CD4+ T cells. We will employ luciferase reporter assays to determine functional variants in the enhancers and promoter of LSP1, perform CRISPR-mediated editing of prioritized IBD-risk eQTLs to define causal variants, and perform CRISPRi and ChIP assays to determine functional enhancers, relevant up-stream regulators and whether the functional LSP1 eQTLs directly perturb the binding of key transcription factors that modulate LSP1 expression. In Aim 2, we will determine the role of LSP1 in reprogramming of CD4+ T cells into the pathogenic state observed in IBD. To determine whether LSP1 influences the differentiation and pathogenic function of CD4+ T cells from healthy and IBD donors, we will reduce and increase LSP1 levels and assess the effects on CD4+ T-cell activation, apoptosis, proliferation and proinflammatory cytokine production. In an adoptive T cell transfer model of colitis, we will compare the ability of Lsp1- sufficient (wild-type) and Lsp1-deficient CD4+ T cells in driving colonic inflammation and pathogenic TH1 and TH17 differentiation. We will determine whether reducing Lsp1 expression in CD4+ T cells enhances their pathogenicity in mouse models of colitis, thus implicating an important T cell-intrinsic role for LSP1 in IBD pathogenesis. Overall, this study, examining the function, expression, activation and regulation of LSP1 in CD4+ T cells, will provide important mechanistic insights into the genetic basis of risk for inflammatory bowel disease.

项目总结/文摘