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.

我们实验室和其他实验室正在进行的分析已经确定了自身蛋白质的新特性，即翻译后蛋白质修饰 (PTM) 可被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的新兴蛋白质。获得 PTM 并成为 B 和 T 细胞自身免疫反应的目标，导致炎症和胰腺病理学中对自身蛋白进行关键修饰的一些例子包括瓜氨酸化、氧化、脱酰胺反应和异天冬氨酰修饰，细胞内自身蛋白质的所有反应已经从人类 β 细胞中鉴定出关键的 PTM 候选物。其他关键候选者将从β细胞衍生的外泌体中鉴定出来，最近被确定为外周血同样重要的是，细胞内的这些 PTM 可能会改变 β 细胞的生物学特性。在本提案中，我们将定义修饰的自身蛋白如何改变。该提案将研究胰腺β细胞中葡萄糖感应和胰岛素分泌的酶途径。多坐标频谱分析 (MIMOSA) 是耶鲁大学首创的一项技术。重大创新，提供内部交叉验证以及 NMR 验证、直接、严格、 MIMOSA 的“多坐标”方面包含了代谢通量的综合综合分析。稳定同位素沿着交叉的代谢途径从代谢物流向代谢物。同位素异构体”方面使用基于 MS/MS 的稳定同位素标记代谢物的离子碎片分析来确定标签的碳特异性位置是本研究的意义和创新之处。通过药物纠正异常，可以恢复 β 细胞功能的途径修饰，以及将自身免疫生物标志物与β细胞功能障碍的途径联系起来。