Human Islet Antigen Discovery and Imaging

人类胰岛抗原的发现和成像

• 批准号: 6873338
• 负责人: Paul E Harris
• 金额: $ 30.53万
• 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 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6873338
• 关键词: NOD mouse; SCID mouse; antibody specificity; antigen antibody reaction; bioimaging /biomedical imaging; biotechnology; clinical research; gene expression; genetic mapping; human tissue; immunoprecipitation; insulin dependent diabetes mellitus; laboratory rat; magnetic resonance imaging; method development; microarray technology; pancreas imaging /visualization; pancreatic islet function; pancreatic islet transplantation; polymerase chain reaction; positron emission tomography; reagent /indicator; surface antigens; tissue /cell culture; transplantation immunology; western blottings

DESCRIPTION (provided by applicant): The overall goal of this proposal is to continue our efforts in developing and validating reagents and methods suitable for imaging human islets in the context of islet transplantation and/or type 1 diabetes (TID). Functional imaging of the endocrine pancreas has been difficult, in part because of the many physiologic roles and cell types that characterize the Islets of Langerhans and the exocrine pancreas. During the past year (10/2002- 2/2004) we have used transcript profiling to obtain a map of the genes expressed by human islet tissue, human exocrine pancreas tissue, and other tissues. Using novel informatics techniques we have identified previously unrecognized candidate markers on islets previously thought to be restricted to neuronal and neuroendocrine tissues. This data has clearly revealed specific molecular/functional overlaps between islet cells and cells of neural and neuroendrocrine lineage, allowing us to now take advantage of a large body of experience and research that has focused on functional imaging of the CNS. On the basis of our efforts in identifying islet specific markers we now propose that targeting beta cell vesicular monoamine transporters, type 2 (VMAT2) with PET radioligands will provide quantitative measurements of beta cell mass and function. We have three specific aims that together are designed to provide the necessary preclinical data to move islet imaging via VMAT2 targeting into clinical trials as expediently as possible. In specific aim one we outline the necessary steps to establish the radiosynthesis of VMAT2 ligands in our PET chemistry laboratory. Specific aim two focuses on expanding our understanding of the ultrastructural and cell biology of vesicular monoamine transporters type 2 as expressed in beta cells. In specific aim three we outline a series of studies in animal models of diabetes and islet transplantation designed to show proof of principle (i.e VMAT2 targeting provides quantitative measurements of beta cell mass useful for the management and study human type 1 diabetes and islet transplantation). We have drawn together an interdisciplinary research team of basic cell biologists, transplant surgeons and experts in nuclear medicine with the common goal of developing of imaging reagents and techniques that distinguish islets from its surroundings and provide quantitative measurements of their mass.

描述（由申请人提供）： 本提案的总体目标是继续努力开发和验证适用于在胰岛移植和/或1型糖尿病（TID）背景下成像人类胰岛的试剂和方法。内分泌胰腺的功能成像一直是困难的，部分原因是由于许多生理作用和细胞类型的特点，胰岛和外分泌胰腺。在过去的一年中（10/2002- 2/2004），我们已经使用转录谱，以获得人类胰岛组织，人类外分泌胰腺组织，和其他组织表达的基因的地图。使用新的信息学技术，我们已经确定了以前未被识别的候选标记胰岛以前被认为是局限于神经元和神经内分泌组织。这些数据清楚地揭示了胰岛细胞与神经和神经内分泌谱系细胞之间的特定分子/功能重叠，使我们现在能够利用大量专注于CNS功能成像的经验和研究。基于我们在识别胰岛特异性标志物方面的努力，我们现在提出，用PET放射性配体靶向β细胞囊泡单胺转运蛋白2型（VMAT 2）将提供β细胞质量和功能的定量测量。我们有三个具体目标，旨在提供必要的临床前数据，以尽可能方便地通过VMAT 2靶向将胰岛成像转移到临床试验中。在具体的目标之一，我们概述了必要的步骤，建立VMAT 2配体的放射性合成在我们的PET化学实验室。具体目标二侧重于扩大我们的理解的超微结构和细胞生物学的囊泡单胺转运蛋白2型在β细胞中表达。在第三个具体目标中，我们概述了一系列在糖尿病和胰岛移植动物模型中的研究，旨在证明原理（即VMAT 2靶向提供对管理和研究人类1型糖尿病和胰岛移植有用的β细胞质量的定量测量）。我们汇集了基础细胞生物学家，移植外科医生和核医学专家的跨学科研究团队，共同目标是开发成像试剂和技术，将胰岛与其周围环境区分开来，并提供其质量的定量测量。