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）：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。更快速评估 T1D 和 T2D 干预措施的一个重要障碍是缺乏合适的胰腺 β 细胞团生物标志物。监测β细胞质量和/或功能的可靠方法将能够实时评估糖尿病的进展以及监测药理学和其他干预措施的功效。该提案解决了这些需求。最近，我们发现了一种可通过正电子发射断层扫描 (PET) 在体内量化的 β 细胞质量生物标志物。 PET 是一种断层扫描成像技术，可对区域放射性配体的吸收和清除进行精确的非侵入性体内动态测量。这些特定放射性标记化合物的动态测量在皮摩尔至纳摩尔范围内敏感，并且可以解卷积为受体浓度的测量。对于 β 细胞质量估计，我们已将 VMAT2（2 型囊泡单胺转运蛋白）确定为生物标志物，将 DTBZ 确定为转运蛋白的配体。相对于内分泌和外分泌胰腺的其他细胞，VMAT2 在人胰腺的 β 细胞中高度表达。因此，胰腺中 DTBZ 放射性配体的摄取和清除的动态测量提供了 VMAT2 浓度的测量和 β 细胞质量的间接测量。此次更新应用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，并使用 T2D 进展的临床前模型以及 T1D 和 T2D 的治疗来提供 PET 扫描的临床实用性的进一步证据。在具体目标一中，我们提出使用 PET 来估计 T2D 啮齿动物模型中的 β 细胞质量的纵向研究。这些研究旨在了解 BCM 的估计如何在 β 细胞质量和功能的代谢扰动下使用 [18F]-FP-DTBZ 进行 PET 扫描。在具体目标二中，利用目标一中提出的见解，我们将在 β 细胞再生的背景下分析 β 细胞的 PET 成像。在具体目标三中，我们将研究 VMAT2 在人类胰腺的一个独特区域（头部后叶）中的组织分布，其中 VMAT2 表达可能延伸到表达胰腺多肽的细胞。在这个目标中，我们将定量 VMAT2 和胰腺多肽的共表达，以确定 VMAT2 与“完美”β 细胞生物标志物的差距有多大。总体而言，目标一、二和三中提出的研究构成了我们正在进行的使用 VMAT2 作为人类健康和疾病中 BCM 生物标志物的临床评估的下一个合乎逻辑的后续步骤。公共健康相关性：世界范围内糖尿病发病率不断上升，加上缺乏适当的身体可测量和真实产生胰岛素的能力的终点，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，我们发现了一种可通过 PET 在体内定量的 β 细胞质量生物标志物。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。无创测量产生胰岛素的β细胞质量的能力对于表征新药和完善这种破坏性疾病的诊断和治疗具有至关重要的价值。