HUMAN ISLET ANTGEN DISCOVERY AND IMAGING

人类胰岛抗原的发现和成像

• 批准号: 8326435
• 负责人: Paul E Harris
• 金额: $ 5.87万
• 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/8326435
• 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; preclinical study; promoter; 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(申请人提供)：1型和2型糖尿病(T1D和T2D)的常见病理基础是β细胞质量(BCM)不足，无法满足代谢需求。对T1D和T2D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岛β细胞团生物标志物。监测β细胞质量和/或功能的可靠手段将能够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。这项建议满足了这些需求。最近，我们发现了一种可以通过正电子发射断层扫描(PET)在体内定量的β细胞质量的生物标志物。PET是一种断层成像技术，它可以在体内无创地动态测量局部放射性配基的摄取和清除。这些对特定放射性化合物的动态测量在微微到纳米摩尔范围内是灵敏的，并且可以解卷积成受体浓度的测量。对于β细胞质量的估计，我们已经确定VMAT2(囊泡单胺转运体类型2)为生物标记物，DTBZ作为转运体的配体。相对于内分泌和外分泌胰腺的其他细胞，VMAT2在人胰腺的β细胞中高表达。因此，动态测量胰腺中DTBZ放射性配基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。这一更新应用的主要目的是更好地了解VMAT2在β细胞中的生物学和生化，并使用T2D进展的临床前模型和T1D和T2D的治疗为PET扫描的临床应用提供进一步的证据。在具体目标一中，我们建议使用正电子发射计算机断层扫描(PET)进行纵向研究，以估计T2D啮齿动物模型中的β细胞质量。这些研究旨在了解BCM使用[18F]-FP-DTBZ进行PET扫描的估计如何在β细胞质量和功能的代谢扰动下执行。在具体的目标二中，利用目标一中提出的见解，我们将在贝塔细胞再生的背景下分析贝塔细胞的PET成像。在特定的目标三中，我们将研究VMAT2在人胰腺一个独特的区域--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。在这个目标中，我们将对VMAT2和胰多肽的共表达进行量化，以确定VMAT2距离成为“完美”的β细胞生物标记物还有多远。总体而言，目标一、目标二和目标三中建议的研究构成了我们正在进行的VMAT2作为BCM生物标记物在人类健康和疾病中的使用的临床评估的下一个合乎逻辑的下一步。与公共卫生相关：世界范围内糖尿病发病率的上升，再加上人体可测量和真实产生胰岛素的能力缺乏合适的终点，构成了卫生保健专业人员和制药业面临的严重限制。最近，我们发现了一种可在活体内用正电子发射计算机断层扫描(PET)进行定量的β细胞质量的生物标志物。本申请提出了一系列研究，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方面的实用性。非侵入性地测量产生胰岛素的β细胞数量的能力将对确定新药的特征以及改进这种毁灭性疾病的诊断和治疗具有关键价值。