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Epigenetic, Protein, and Cellular Biomarkers of Beta Cell Function in T1D

T1D β 细胞功能的表观遗传、蛋白质和细胞生物标志物

基本信息

批准号：
8813784
负责人：
Kevan C Herold
金额：
$ 249.68万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-18 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8813784
关键词：
Address Affect Allogenic Area Autoantigens Autoimmune Process Beta Cell Biological Biological Markers Biological Models Cell Death Cell Nucleus Cell Proliferation Cell physiology Cell surface Cells Cellular Immunity Cellular Stress Cessation of life Characteristics Chronic Clinical Clinical Trials Collaborations DNA Development Diabetes Mellitus Differentiation Antigens Disease Disease Progression Disease model Elements Epigenetic Process Event Functional disorder Funding Opportunities Gene Expression Genes Genetic Genome Glucose Goals Health Human Human Pathology Hyperglycemia Immune Immune response Immunologics Individual Inflammation Inflammation Mediators Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Intravenous Investigation Islet Cell Islets of Langerhans Laboratories Lead Link Measurement Metabolic Metabolic stress Methodology Methylation Modeling Modification Molecular Monitor Mus Oral Outcome Pathogenesis Pathway interactions Patient Care Patients Phenotype Pilot Projects Post-Translational Protein Processing Process Production Property Protein Isoforms Proteins Proteomics Research Research Personnel Risk Sampling Serological Serum Staging Stress System Testing Therapeutic Uses Tissues Translating Work candidate identification cell dedifferentiation cell killing environmental stressor extracellular in vivo interest islet metabolic abnormality assessment novel pre-clinical prevent progenitor public health relevance response tool type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): Progressive loss of beta cell function is the hallmark of Type 1 diabetes (T1D). Elements of both metabolic and autoimmune markers are known in patients with T1D, although features of early, pre-clinical disease are less well understood. Studies proposed herein combine the unique and complementary expertise of three laboratories with the goal of defining specific parameters during the dysfunction and eventual demise of beta cells, though those cells are asymptomatic in subjects at-risk for T1D. Presented below, our investigators have identified specific biomarkers of beta cells in three important areas, including epigenetics, in the modification of cellular proteins under conditions of stress, and in the identification of unique phenotypes of beta cells that undergo dedifferentiation. There is an important and natural synergy between these three areas of investigation that will better define the changes in beta cells from the nucleus to the cell surface over the course of disease. In all studies, human beta cells will be examined ex vivo in parallel with murine systems to model the metabolic and inflammatory stress of T1D. First, we have identified increased levels of unmethylated insulin DNA (INS), which is of beta cell origin, in the serum of human patients indicating beta cell killing during the preclinical period of the disease. Similar approaches will extend these observations to intracellular genetic methylation events linked to beta cell stress. Second, we have identified specific posttranslational protein modifications (PTMs) in beta cells as well as extracellular products of beta cells in murine models of disease. These observations will now be examined in human islet cells under various conditions of inflammation and dedifferentiation. Finally, we have identified dedifferentiation of beta cells in settings of metabolic stress and postulate that similar changes in the differentiation state occur during development of T1D. The latter observations indicate that beta cells may undergo developmental changes, but not necessarily death, in the development of disease. In our proposed studies, we will evaluate changes in these parameters in a common model system reflecting the immunologic stress that characterizes T1D. We will integrate the findings in order to develop a defined pathway of markers associated with beta cell stress and death. Finally, we will test whether the information we have gathered from our studies can be used as biomarkers using samples obtained from patients with Type 1 diabetes and those at-risk who participated in the DPT-1. Our proposed studies may lead to new understanding of the biologic changes leading to beta cell death in diabetes and ways in which this information can be used to monitor disease activity and guide the use of therapeutics.

描述(申请人提供)：进行性的β细胞功能丧失是1型糖尿病(T1D)的标志。新陈代谢和自身免疫标记物的成分在T1D患者中都是已知的，尽管早期临床前疾病的特征还不太清楚。这里提出的研究结合了三个实验室独特和互补的专业知识，目标是确定β细胞功能障碍和最终死亡期间的特定参数，尽管这些细胞在T1D的风险受试者中是无症状的。如下所示，我们的研究人员已经在三个重要领域确定了β细胞的特定生物标记物，包括表观遗传学，在应激条件下对细胞蛋白质的修饰，以及对经历去分化的β细胞的独特表型的鉴定。这三个研究领域之间存在着重要而自然的协同作用，这将更好地定义β细胞在疾病过程中从细胞核到细胞表面的变化。在所有研究中，人类β细胞将与小鼠系统并行进行体外检测，以模拟T1D的代谢和炎症应激。首先，我们已经确定了人类患者血清中非甲基化胰岛素DNA(INS)水平的增加，这表明在疾病的临床前阶段，β细胞被杀死。类似的方法将将这些观察扩展到与β细胞应激有关的细胞内基因甲基化事件。其次，我们已经在小鼠疾病模型中确定了贝塔细胞和贝塔细胞胞外产物中特定的翻译后蛋白修饰(PTM)。这些观察结果现在将在各种炎症和去分化条件下的人类胰岛细胞中进行检验。最后，我们确定了在代谢应激环境下β细胞的去分化，并假设在T1D的发育过程中，分化状态也发生了类似的变化。后者的观察表明，在疾病的发展过程中，β细胞可能会经历发育变化，但不一定会死亡。在我们提出的研究中，我们将在一个反映T1D特征的免疫应激的通用模型系统中评估这些参数的变化。我们将整合这些发现，以开发与β细胞应激和死亡相关的标记物的明确途径。最后，我们将使用从参与DPT-1的1型糖尿病患者和高危患者那里获得的样本来测试我们从研究中收集的信息是否可以用作生物标记物。我们提出的研究可能会导致对导致糖尿病患者β细胞死亡的生物学变化的新理解，以及如何利用这些信息来监测疾病活动并指导治疗药物的使用。