HUMAN ISLET ANTGEN DISCOVERY AND IMAGING

人类胰岛抗原的发现和成像

• 批准号: 7728539
• 负责人: Paul E Harris
• 金额: $ 38.47万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728539
• 关键词: Address; Area; Asses; Beta Cell; Binding; Biochemistry; Biological Markers; Biology; Cells; Clinical; Data; Diabetes Mellitus; Diagnosis; Disease; Disease Progression; Drug Industry; Drug or chemical Tissue Distribution; EGF gene; Endocrine; Evaluation; Exocrine pancreas; Functional disorder; Gastrins; Genes; Glucagon; Gold; Growth and Development function; Head; Head of pancreas; Health; Health Professional; Human; Hyperglycemia; Image; Imaging Techniques; Incidence; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intervention; Investigation; Islets of Langerhans; Ligands; Literature; Lobe; Longitudinal Studies; Measurable; Measurement; Measures; Metabolic; Methods; Minor; Modeling; Monitor; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Pancreatic Polypeptide; Pathology; Patients; Pharmaceutical Preparations; Population; Positron-Emission Tomography; Pre-Clinical Model; Rattus; Regulatory Element; Relative (related person); Research Design; Rodent; Rodent Model; Series; Signal Transduction; Somatostatin; Staining method; Stains; Structure of beta Cell of islet; Techniques; Time; Tissues; Work; base; diabetes mellitus therapy; diabetic; falls; glucose tolerance; in vivo; insight; insulin secretion; islet; longitudinal positron emission tomography; meetings; morphometry; nano; polypeptide; preclinical study; promoter; public health relevance; radioligand; receptor; research clinical testing; research study; type I and type II diabetes; uptake; vesicular monoamine transporter

DESCRIPTION (provided by applicant): The common pathology underlying both type 1 and type 2 diabetes (T1D and T2D) is insufficient beta-cell mass (BCM) to meet metabolic demands. An important impediment to the more rapid evaluation of interventions for both T1D and T2D is lack of suitable biomarkers of pancreatic beta cell mass. A reliable means of monitoring the mass and/or function of beta cells would enable evaluation of the progression of diabetes in real time as well as the monitoring the efficacy of pharmacologic and other interventions. This proposal addresses these needs. Recently, we identified a biomarker of beta cell mass that is quantifiable in vivo by Positron Emission Tomography (PET). PET is a tomographic imaging technique, which allows for accurate non-invasive in vivo dynamic measurements of regional radioligand uptake and clearance. These dynamic measurements of specific radiolabled compounds are sensitive in the pico- to nano-molar range and can be deconvoluted into measurements of receptor concentration. For beta cell mass estimates, we have identified VMAT2 (vesicular monoamine transporter type 2) as the biomarker and DTBZ as the transporter's ligand. VMAT2 is highly expressed in beta cells of the human pancreas relative to other cells of the endocrine and exocrine pancreas. Thus dynamic measurements of the uptake and clearance of DTBZ radioligands in the pancreas provide a measure of VMAT2 concentrations and an indirect measurement of beta cell mass. The primary aim of this renewal application is to better understand the biology and biochemistry of VMAT2 in beta cells and to provide further evidence of the clinical utility of PET scans using preclinical models of progression of T2D and therapy of T1D and T2D. In Specific Aim One we propose longitudinal studies using PET to estimate beta cell mass in a rodent models of T2D. These studies are designed to understand how estimates of BCM made PET scans with [18F]-FP-DTBZ perform under metabolic perturbations of beta cell mass and function. In Specific Aim Two, using insights developed in Aim one, we will analyze PET imaging of beta cells in the context of beta cell regeneration. In Specific Aim Three, we will study the tissue distribution of VMAT2 in a unique area of the human pancreas, the posterior lobe of the head, where VMAT2 expression may extend to cells expressing pancreatic polypeptide. In this Aim we will quantitate the co-expression of VMAT2 and pancreatic polypeptide to determine how far astray VMAT2 falls from being the "perfect" beta cell biomarker. Overall, the proposed studies in Aims one, two and three constitute the next logical next steps in our ongoing clinical evaluation of the use of VMAT2 as biomarker of BCM in human health and disease. PUBLIC HEALTH RELEVANCE: The rising world-wide incidence of diabetes, combined with the lack of suitable endpoints of the body's measurable and true capacity to produce insulin, constitute a serious restriction facing health care professionals and the pharmaceutical industry. Recently, we identified a biomarker of beta cell mass that is quantifiable in vivo by PET. This application proposes a series of studies aimed at validating the utility of this technique in monitoring diabetic disease progression in a non-invasive real time manner. The ability to noninvasively measure the mass of insulin producing beta cells will be of critical value towards characterizing new drugs and refining the diagnosis and treatment of this devastating disease.

描述（由申请人提供）：1型和2型糖尿病（T1D和T2D）的共同病理是β细胞质量（BCM）不足以满足代谢需求。对T1D和T2D的干预措施进行更快速评估的一个重要障碍是缺乏合适的胰腺细胞质量生物标志物。一种监测β细胞质量和/或功能的可靠方法将使实时评估糖尿病的进展以及监测药物和其他干预措施的效果成为可能。本提案解决了这些需求。最近，我们发现了一种β细胞质量的生物标志物，可以通过正电子发射断层扫描（PET）在体内量化。PET是一种层析成像技术，它允许对区域放射性配体摄取和清除进行精确的非侵入性体内动态测量。这些特定放射性化合物的动态测量在皮到纳米摩尔范围内是敏感的，并且可以反卷积到受体浓度的测量中。对于β细胞质量的估计，我们已经确定了VMAT2（水泡单胺转运蛋白2型）作为生物标志物，DTBZ作为转运蛋白的配体。相对于其他内分泌和外分泌胰腺细胞，VMAT2在人类胰腺的β细胞中高度表达。因此，动态测量胰腺中DTBZ放射性配体的摄取和清除提供了VMAT2浓度的测量和β细胞质量的间接测量。这项更新申请的主要目的是更好地了解β细胞中VMAT2的生物学和生物化学，并通过临床前T2D进展模型以及T1D和T2D的治疗，为PET扫描的临床应用提供进一步的证据。在具体目的一，我们提出纵向研究使用PET估计β细胞质量在啮齿动物模型的T2D。这些研究旨在了解在β细胞质量和功能的代谢扰动下，用[18F]-FP-DTBZ进行PET扫描对BCM的估计是如何进行的。在特定目标2中，使用目标1中开发的见解，我们将在β细胞再生的背景下分析β细胞的PET成像。在特异性目标3中，我们将研究VMAT2在人类胰腺的一个独特区域，即头部后叶的组织分布，在那里VMAT2的表达可能延伸到表达胰腺多肽的细胞。在本研究中，我们将量化VMAT2和胰腺多肽的共表达，以确定VMAT2离“完美”的β细胞生物标志物有多远。总的来说，目标1、2和3中的拟议研究构成了我们正在进行的VMAT2作为BCM在人类健康和疾病中的生物标志物的临床评估的下一个合乎逻辑的下一步。公共卫生相关性：世界范围内糖尿病发病率的上升，加上缺乏适当的人体可测量和真实胰岛素生产能力的终点，构成了卫生保健专业人员和制药行业面临的严重限制。最近，我们发现了一种β细胞质量的生物标志物，可以通过PET在体内量化。该应用程序提出了一系列旨在验证该技术在以非侵入性实时方式监测糖尿病疾病进展中的效用的研究。无创测量产生胰岛素的β细胞质量的能力将对描述新药和改进这种毁灭性疾病的诊断和治疗具有关键价值。