Transcriptional regulation by O-GlcNAcylation in T lymphocytes

T 淋巴细胞中 O-GlcNAc 酰化的转录调节

基本信息

批准号：
9251750
负责人：
Parameswaran Ramakrishnan
金额：
$ 39.63万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9251750
关键词：
Adverse effects Affect Area Arthritis Autoimmune Diabetes Autoimmune Diseases Autoimmune Process Autoimmunity Bacterial Artificial Chromosomes Biological Assay Blindness Bone Marrow C57BL/6 Mouse CD4 Positive T Lymphocytes Celiac Disease Cell physiology Cells Child Chronic DNA Biochemistry Data Development Diabetes Mellitus Diagnosis Disease Disease model FOXP3 gene Foundations Gene Expression Gene Expression Profiling Gene Targeting Genes Genetic Transcription Granulocyte-Macrophage Colony-Stimulating Factor Heart Human Hyperglycemia Immune Immunosuppression Immunosuppressive Agents Impairment Inbred NOD Mice Insulin-Dependent Diabetes Mellitus Interferon Type II Interleukin-2 Jurkat Cells Kidney Failure Knockout Mice Lead Lupus Mediating Molecular Molecular Target Monoclonal Antibodies Mus NF-kappa B Nerve Nuclear Pathogenesis Pathologic Patients Pharmaceutical Preparations Physiological Post-Translational Protein Processing Process Protein Biochemistry Proteins Reagent Receptor Activation Regulation Research Role Serine Specificity T cell response T-Cell Receptor T-Lymphocyte Therapeutic Threonine To autoantigen Transcriptional Activation Transcriptional Regulation Transforming Growth Factor beta Transgenic Mice Transgenic Organisms base c new chromatin immunoprecipitation cytokine experimental study forkhead protein glucose metabolism in vivo molecular drug target mouse model mutant novel public health relevance reconstitution sugar therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): Hyperglycemia is a hallmark of diabetes. Adverse pathological effects of hyperglycemia include the increased posttranslational modification of cellular proteins at serine and threonine residues by the sugar N- acetylglucosamine, in a process termed O-GlcNAcylation. We found that the transcription factor nuclear factor- kappaB (NF-κB) subunit, c-Rel, is a target for this pathologic O-GlcNAcylation. Our preliminary data shows that c-Rel is O-GlcNAcylated at serine residue 350 in T lymphocytes. c-Rel is the major regulator of T cell function and T regulatory (T reg) cell development that controls autoimmunity and immunosuppression, respectively. We found that c-Rel O-GlcNAcylation increases its transcriptional activity and the expression of pro- autoimmune cytokines interleukin-2 (IL-2) and interferon gamma (IFNG), and decreases the expression of the transcription factor, forkhead box P3 (FOXP3) in T cells. Based on this, we hypothesize that O-GlcNAcylation of c-Rel serves as a key regulatory switch with dual roles in controlling transcription in T cells and T reg cells promoting autoimmunity in type 1 diabetes. Here, we propose to study the role of c-Rel O-GlcNAcylation in (1) the transcriptional regulation of proautoimmune cytokines and T cell function (2) regulation of FOXP3 transcription, T reg cell development and immunosuppression and (3) T cell-mediated autoimmunity using non- GlcNAcylatable c-Rel expressing non obese diabetic (NOD) mouse model. This study explores the emerging area of immunometabolism. It reveals c-Rel O-GlcNAcylation as a novel glucose metabolism-dependent molecular mechanism that regulates autoimmunity. Inhibition of total NF-kappaB elicits broad side effects and despite decades of research, drugs based on molecular targets to treat type 1 diabetes have remained elusive. Therefore, understanding unique post-translational modifications such as O-GlcNAcylation, that NF-kappaB undergoes, could prove a potential therapeutic target and lead to develop drugs with higher specificity. Moreover, this study serves as the basis to explore the role of c-Rel O-GlcNAcylation in other autoimmune diseases such as celiac disease, lupus and arthritis, where c-Rel function has been implicated.

描述（由申请人证明）：高血糖是糖尿病的标志。 κB）亚基C-Rel是O-Glcnacylation的一个靶标，C-Rel在丝氨酸残基350中是T淋巴细胞中的O-GlcnacyLalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalalailation c-C-C-C- RES是T细胞功能的主要规则（T）控制自身免疫性和免疫的细胞发育。因子，forkhead box p3（foxp3）在T细胞中（1）o-Glcnacylation（1）promune细胞因子和T细胞功能的转录调节（2）FOXP3转录，T reg细胞发育和免疫传播的调节以及（3）T细胞介导的自身免疫，使用非glcncylable-rel表达非肥胖的糖尿病 - 糖尿病 - （点头）小鼠模型。治疗型糖尿病仍然难以捉摸。 Rel O-Glcnacylation在肠胃疾病，狼疮和关节炎等耳鼻喉科疾病中的作用是C-REL功能。