Posttranslational Neoantigens in Autoimmunity and Metabolism in T1D

翻译后新抗原在 T1D 自身免疫和代谢中的作用

基本信息

批准号：
10588351
负责人：
Richard G Kibbey
金额：
$ 74.77万
依托单位：
YALE UNIVERSITY
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：
2023-01-25 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10588351
关键词：
Affect Antibodies Appearance Asparagine Aspartic Acid Attention Autoimmune Autoimmune Diseases Autoimmune Responses Autoimmunity B-Lymphocytes Beta Cell Binding Sites Biochemical Biological Biological Assay Biological Markers Carbon Cell physiology Cells Cellular Metabolic Process Characteristics Chronic Citrulline Clinical Data Development Enzymes Exposure to Extracellular Space Functional disorder Glucokinase Glucose Glycolysis Health Human Human body Immune response Immunity Immunologic Markers In Vitro Individual Inflammation Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Ions Islets of Langerhans Isoaspartic Acid Label Laboratories Link Location Maps Mass Spectrum Analysis Metabolic Metabolic Pathway Metabolic dysfunction Metabolism Mind Modification Mus Outcome Pancreas Pathology Pathway interactions Patients Peptides Peripheral Pharmacologic Substance Phosphorylation Pilot Projects Positioning Attribute Post-Translational Protein Processing Process Production Property Protein Chemistry Protein Isoforms Proteins Proteome Proteomics Reaction Reactive Oxygen Species Sentinel Serology Shapes Site Stable Isotope Labeling Stress Structure Structure of beta Cell of islet T cell response T-Lymphocyte Technology Therapeutic Time Tissues Universities Work cytokine deamidation early onset exosome glycosylation immunogenic induced pluripotent stem cell inhibitor innovation insulin secretion islet mitochondrial metabolism molecular modeling neoantigens non-diabetic novel oxidation repaired response stable isotope

项目摘要

Ongoing analyses from our laboratory and others have identified novel properties of self proteins, namely posttranslational protein modifications (PTMs) that may be identified as early proteomic and immunologic biomarkers of Type 1 diabetes as well as alter metabolic pathways. An emerging number of self proteins acquire PTMs and become targets of B and T cell autoimmune responses leading to inflammation and pathology in the pancreas. Some examples of critical modifications to self proteins include citrullination, oxidation, deamidation reactions, and isoaspartyl modification, all responses of self proteins within cells that undergo inflammatory stress. Key PTM candidates have already been identified from human beta cells and other key candidates will be identified from beta cell derived exosomes, recently identified as a peripheral marker of beta cell health. As importantly, these PTMs within cells may alter the biological properties of proteins within beta cells. In the present proposal, we will define how modified self-proteins may alter enzymatic pathways of glucose sensing and insulin secretion in the pancreatic beta cell. The proposal will utilize MultiOrdinate Spectral Analysis (MIMOSA), a technology pioneered at Yale University. MIMOSA is a major innovation that provides an internally cross-validated as well as NMR-validated, direct, rigorous, comprehensive integrated analysis of metabolic fluxes. The “multi-ordinate” aspect of MIMOSA incorporates the flow of stable isotope from metabolite to metabolite along intersecting metabolic pathways. The “mass isotopomer” aspect uses MS/MS-based ion fragmentation analysis of stable-isotope-labeled metabolites to identify the carbon-specific position of label. The significance and innovation of the present studies is in identifying pathways that may restore beta cell functions, via pharmaceutical correction of the aberrant modification, as well as link autoimmune biomarkers with pathways of beta cell dysfunction.

我们实验室和其他人正在进行的分析已经确定了自我蛋白质的新特性，即翻译后蛋白质修饰（PTM），可以鉴定为早期蛋白质组学和免疫学 1型糖尿病的生物标志物以及改变代谢途径。新兴的自我蛋白质数量获取PTM并成为B和T细胞自身免疫反应的靶标，导致注射和胰腺中的病理学。对自我蛋白质进行批判性修饰的一些例子包括柠檬化，氧化，死亡反应和异冬型修饰，在细胞中自蛋白的所有反应承受炎症压力。已经从人类beta细胞中鉴定出了关键的PTM候选者，其他关键候选者将从beta细胞衍生的外泌体中识别，最近被确定为外围 β细胞健康的标记。重要的是，细胞内的这些PTM可能会改变 β细胞中的蛋白质。在本提案中，我们将定义修改后的自我蛋白如何改变胰腺β细胞中葡萄糖敏感性和胰岛素分泌的酶促途径。提案将利用耶鲁大学开创性的技术多层光谱分析（Mimosa）。含羞草是一个主要创新提供了内部交叉验证以及NMR验证，直接，严格，代谢通量的全面综合分析。 Mimosa Incorporated的“多边形”方面稳定的同位素从代谢产物到代谢物沿着相交的代谢途径的流动。 “质量” 同位素方面的方面使用基于MS/MS的离子片段化分析稳定 - 同位素标记的代谢物确定标签的碳特异性位置。当前研究的重要性和创新在于通过药物校正，识别可能恢复β细胞功能的途径修改以及将自身免疫性生物标志物与β细胞功能障碍的途径联系起来。