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（由申请人提供）：类型1和2型糖尿病（T1D和T2D）的基础病理学是不足的β细胞质量（BCM），无法满足代谢需求。对T1D和T2D的干预措施更快评估的重要障碍是缺乏胰腺β细胞量的合适生物标志物。监测β细胞的质量和/或功能的可靠手段，可以实时评估糖尿病的进展以及监测药理和其他干预措施的疗效。该建议解决了这些需求。最近，我们确定了β细胞量的生物标志物，该β细胞量可以通过正电子发射断层扫描（PET）在体内进行量化。 PET是一种层析成像技术，它允许对区域放射性吸收和清除率进行准确的非侵入性体内动态测量。这些对特定放射性化合物的动态测量在PICO-至纳米摩尔范围内是敏感的，可以将其解卷为受体浓度的测量。对于β细胞质量估计，我们将VMAT2（囊泡单胺转运蛋白2型）确定为生物标志物，而DTBZ为转运蛋白的配体。 VMAT2相对于内分泌和外分泌胰腺的其他细胞，在人胰腺的β细胞中高度表达。因此，胰腺中DTBZ放射性体的摄取和清除率的动态测量提供了VMAT2浓度的度量​​和β细胞质量的间接测量。这种更新应用的主要目的是更好地了解Beta细胞中VMAT2的生物学和生物化学，并使用T2D进展的临床前模型以及T1D和T2D的治疗提供了PET扫描临床实用性的进一步证据。在特定目标中，我们提出了使用PET估算T2D啮齿动物模型中β细胞量的纵向研究。这些研究旨在了解BCM的估计如何通过[18F] -FP-DTBZ在β细胞质量和功能的代谢扰动下进行PET扫描。在特定的目标二中，使用目标一个目标的见解，我们将在β细胞再生的背景下分析β细胞的PET成像。在特定的目标三中，我们将研究VMAT2在人胰腺的独特区域（头部的后叶）中的组织分布，其中VMAT2表达可能延伸至表达胰多肽的细胞。在此目标中，我们将量化VMAT2和胰多肽的共表达，以确定误入歧途VMAT2与“完美” beta beta细胞生物标志物相差多远。总体而言，在目标一，二和第三的目标中提出的研究构成了我们对使用VMAT2作为BCM在人类健康和疾病中的生物标志物的持续临床评估中的下一个逻辑下一步。公共卫生相关性：糖尿病的全球发病率上升，加上人体可测量和真实产生胰岛素的能力的合适终点，构成了医疗保健专业人员和制药行业面临的严重限制。最近，我们确定了beta细胞量的生物标志物，该β细胞质量可以在体内量化PET。该应用提出了一系列研究，旨在验证该技术以非侵入性实时方式监测糖尿病疾病进展的实用性。非侵入性测量产生β细胞的质量的能力将对表征新药并完善这种毁灭性疾病的诊断和治疗具有至关重要的价值。