Biomarker of IAPP dysfunction in prediabetes and early type 2 diabetes mellitus (T2DM)

糖尿病前期和早期 2 型糖尿病 (T2DM) 中 IAPP 功能障碍的生物标志物

基本信息

批准号：
10079720
负责人：
PAUL GUYRE
金额：
$ 29.92万
依托单位：
CELDARA MEDICAL, LLC
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：
2020-09-11 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10079720
关键词：
Affect Affinity American Amyloid Amyloid deposition Animal Model Antigens Benchmarking Beta Cell Binding Proteins Biological Assay Biological Markers Blood Blood specimen Caring Cell Death Cell physiology Chronic Complex Deposition Detection Development Diabetes Mellitus Diagnostic Diagnostic tests Dietary Intervention Disease Disease Progression Early Diagnosis Early treatment Effectiveness Engineering Ensure Enzyme-Linked Immunosorbent Assay Epitopes Functional disorder Future Glucose Glycosylated hemoglobin A Human Immunize Individual Insulin Insulin Resistance Intervention Islets of Langerhans Kinetics Legal patent Letters Life Style Modification Measures Metformin Molecular Chaperones Molecular Conformation Monitor Monoclonal Antibodies Mus Non-Insulin-Dependent Diabetes Mellitus Pancreas Pancreatic Hormones Pathogenicity Patient Care Patients Peptides Pharmaceutical Preparations Phase Plasma Population Prediabetes syndrome Proteins Public Health Reproducibility Risk Sampling Screening Result Sensitivity and Specificity Serum Specificity Structure Structure of beta Cell of islet Technology Testing Therapeutic Therapeutic Intervention Time Toxic effect United States amyloid formation base burden of illness clinical diagnostics cost design diabetic patient early detection biomarkers fasting plasma glucose high risk innovation insulin secretion islet islet amyloid polypeptide monomer novel novel strategies nucleobindin pandemic disease patient population peripheral blood preservation prevent response success tool

项目摘要

Project Summary Type 2 diabetes mellitus (T2DM) is a major unmet public health concern with an annual cost in the United States of over 300 billion dollars, according to the American Diabetes Association. Approximately 25% of the U.S. population is considered prediabetic, or at high risk of developing T2DM. Human islet amyloid polypeptide (hIAPP, or amylin) is a pancreatic hormone co-expressed and secreted with insulin in response to high glucose concentrations. hIAPP has a strong propensity to misfold and aggregate, causing amyloid formation in the islets which results in pancreatic β-cell death and decreased insulin secretion. A significant unmet challenge associated with early detection of hIAPP aggregates is the ability to detect misfolded hIAPP protein versus the natively folded and functional monomeric peptides. In this Phase I application we will develop a first in-kind assay derived from our innovative ‘cap and trap’ technology that provides the capacity to discriminate between misfolded hIAPP and native functional amylin. From this platform we will identify the top 3 highest affinity monoclonal antibodies that will be utilized for an ELISA-based diagnostic in order allow early detection of amyloidogenic hIAPP prior to complete amyloid- dependent β-cell toxicity and insulin-dependent T2DM. The assay will be designed to specifically recognize and quantitate levels of protofibril as opposed to native hIAPP in blood samples of prediabetic and diabetic patients. The immediate impact on the patient population will be the early detection of pathogenic β-cell-derived amyloid protofibrils as a new indicator of prediabetes or early signs of T2DM, as well as a valuable assay for monitoring the effectiveness of drug or dietary interventions.

项目概要 2 型糖尿病 (T2DM) 是一个未得到满足的重大公共卫生问题，在美国每年造成高昂的费用据美国糖尿病协会称，这一数字超过 3000 亿美元，约占美国的 25%。人群被认为是糖尿病前期或患 T2DM 的高风险人群。（hIAPP，或胰淀素）是一种胰腺激素，与胰岛素共同表达和分泌，以应对高葡萄糖 hIAPP 具有强烈的错误折叠和聚集倾向，导致胰岛中淀粉样蛋白的形成。这会导致胰腺 β 细胞死亡和胰岛素分泌减少，这是一个未解决的重大挑战。与 hIAPP 聚集体的早期检测相关的是检测错误折叠的 hIAPP 蛋白与天然折叠和功能性单体肽。在这一阶段的应用中，我们将开发第一个源自我们创新的“帽与捕集器”的实物测定法该技术提供了区分错误折叠的 hIAPP 和天然功能胰岛淀粉样蛋白的能力。从这个平台上，我们将确定前 3 种最高亲和力的单克隆抗体，这些抗体将用于基于 ELISA 的诊断，以便在完全淀粉样蛋白生成之前及早检测出淀粉样蛋白生成 hIAPP 该检测方法旨在特异性识别和检测依赖型 β 细胞毒性和胰岛素依赖型 T2DM。定量糖尿病前期和糖尿病患者血液样本中原纤维的水平，而不是天然 hIAPP。对患者群体的直接影响将是早期检测致病性 β 细胞衍生淀粉样蛋白原纤维作为糖尿病前期或 T2DM 早期症状的新指标，也是一种有价值的监测检测方法药物或饮食干预的有效性。