Responses to Hybrid Insulin Peptides as Biomarkers of Disease Activity in Human Type 1 Diabetes

混合胰岛素肽作为人类 1 型糖尿病疾病活动生物标志物的反应

基本信息

批准号：
10624859
负责人：
Rocky Lee Baker
金额：
$ 38.88万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-02 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624859
关键词：
Antigens Autoantibodies Autoantigens Autoimmune Diabetes Autoimmune Diseases Autoimmunity Beta Cell Biological Markers C-Peptide CD4 Positive T Lymphocytes Cells Chromogranin A Clinical Data Diabetes Mellitus Diagnosis Disease Family Generations Goals Hot Spot Human Hybrids Immune Immunology Inbred NOD Mice Individual Inflammatory Injury Insulin Insulin-Dependent Diabetes Mellitus Investigation Knowledge Left Ligands Microbiology Mus Natural History Nature Onset of illness Organ Organ Donor Patients Peptide Fragments Peptides Peripheral Blood Mononuclear Cell Phenotype Play Post-Translational Protein Processing Process Proteins Publishing Research Residual state Risk Role Secretory Vesicles Site Specificity Structure of beta Cell of islet T cell response T-Lymphocyte Testing autoimmune pathogenesis autoreactive T cell cohort design disease natural history effector T cell enzyme linked immunospot assay human disease improved insulin dependent diabetes mellitus onset islet islet amyloid polypeptide islet cell antibody medical schools mouse model neoantigens neuropeptide Y predictive marker prospective protein aminoacid sequence response single-cell RNA sequencing

项目摘要

Abstract: T Cell Responses to Hybrid Insulin Peptides as Biomarkers of Disease Activity in Type 1 Diabetes An important objective in T1D research is the investigation of autoantigens that activate effector T cells and trigger the inflammatory process in islet beta-cells. We recently identified Hybrid Insulin Peptides (HIPs) as a new class of autoantigens in type 1 diabetes (T1D). These neoantigens are created by the fusion of insulin fragments with peptides from other secretory granule proteins such as chromogranin A (ChgA), islet amyloid polypeptide (IAPP), neuropeptide Y (NPY) or insulin itself. Because insulin is present only in pancreatic beta cells, this discovery might provide an explanation for organ-specific autoimmunity in T1D. Importantly, CD4 T cells responding to HIPs have been isolated from the islets of deceased T1D patients, demonstrating the relevance of these autoantigens to the human disease. We hypothesize that T cells reactive to HIPs can serve as biomarkers of disease. Our goals in this project are (1) to characterize T cell responses to HIPs in the PBMCs of T1D and controls; (2) to determine the extent of reactivity to insulin B:9-23 Hybrid Insulin Peptides in recent onset T1D patients; (3) Investigate the presence and phenotype of HIP-reactive T cells in the natural history of T1D.

摘要：T细胞对杂化胰岛素肽作为疾病活性生物标志物的T细胞反应 1型糖尿病 T1D研究的一个重要目标是对激活效应T细胞的自身抗原的研究并触发胰岛β细胞中的炎症过程。我们最近确定了混合胰岛素肽（臀部）作为1型糖尿病（T1D）的新型自动抗原。这些新抗原是由胰岛素片段与其他分泌颗粒蛋白（如铬甘氨酸）的肽融合 A（CHGA），胰岛淀粉样多肽（IAPP），神经肽Y（NPY）或胰岛素本身。因为胰岛素是该发现仅在胰腺β细胞中出现，可能会提供特定器官特异性的解释 T1D中的自身免疫性。重要的是，已经从胰岛分离出对臀部的CD4 T细胞已经分离出来已故的T1D患者，证明了这些自身抗原与人类疾病的相关性。我们假设T细胞对臀部充电可以用作疾病的生物标志物。我们的目标项目（1）表征T细胞对T1D和对照组的PBMC中臀部的反应；（2）至确定最近发作T1D患者对胰岛素B的反应性程度：9-23杂交胰岛素肽；（3）研究T1D自然史上嘻哈T细胞的存在和表型。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chromogranin A Deficiency Confers Protection From Autoimmune Diabetes via Multiple Mechanisms.

DOI：
10.2337/db21-0513
发表时间：
2021-12
期刊：
Diabetes
影响因子：
7.7
作者：
Srivastava N;Hu H;Vomund AN;Peterson OJ;Baker RL;Haskins K;Teyton L;Wan X;Unanue ER
通讯作者：
Unanue ER

Insulin B-chain hybrid peptides are agonists for T cells reactive to insulin B:9-23 in autoimmune diabetes.

DOI：
10.3389/fimmu.2022.926650
发表时间：
2022
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
通讯作者：

Characterization of Human CD4 T Cells Specific for a C-Peptide/C-Peptide Hybrid Insulin Peptide.

DOI：
10.3389/fimmu.2021.668680
发表时间：
2021
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Wiles TA;Hohenstein A;Landry LG;Dang M;Powell R;Guyer P;James EA;Nakayama M;Haskins K;Delong T;Baker RL
通讯作者：
Baker RL