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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.

项目摘要在美国，2型糖尿病（T2DM）是一个主要的未得到满足的公共卫生问题，每年的费用超过3000亿美元，根据美国糖尿病协会。大约25%的美国人群被认为是前驱糖尿病，或处于发生T2DM的高风险中。人胰岛淀粉样多肽胰淀素（hIAPP，或胰淀素）是一种胰腺激素，与胰岛素共同表达和分泌，以响应高葡萄糖浓度的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导致胰腺β细胞死亡和胰岛素分泌减少。一个尚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蛋白相对于未折叠的hIAPP蛋白的能力。天然折叠和功能性单体肽。在第一阶段的应用中，我们将开发第一种来自我们创新的“帽和陷阱”的实物检测方法。该技术提供了区分错误折叠的hIAPP和天然功能性胰淀素的能力。从该平台，我们将鉴定将用于免疫治疗的前3种最高亲和力的单克隆抗体。基于ELISA的诊断，以允许在完全淀粉样蛋白之前早期检测淀粉样蛋白生成hIAPP，依赖性β细胞毒性和胰岛素依赖性T2DM。该检测试剂盒将被设计为特异性识别和在糖尿病前期和糖尿病患者的血液样品中定量与天然hIAPP相对的原纤维水平。对患者群体的直接影响将是早期发现致病性β细胞源性淀粉样蛋白原纤维作为糖尿病前期或T2DM早期体征的新指标，以及用于监测的有价值的测定药物或饮食干预的有效性。