Human Islet Antigen Discovery and Imaging

人类胰岛抗原的发现和成像

• 批准号: 7106497
• 负责人: Paul E Harris
• 金额: $ 29.81万
• 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 2009-07-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7106497
• 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）： 该提案的总体目标是继续我们在胰岛移植和/或1型糖尿病（TID）的背景下开发和验证适合成像人类小岛的试剂和方法的努力。内分泌胰腺的功能成像很困难，部分原因是特征了Langerhans和外分泌胰腺胰岛的许多生理作用和细胞类型。在过去的一年中（10/2002-2/2004），我们使用了转录物分析来获得人类胰岛组织，人外分泌胰腺组织和其他组织表达的基因图。使用新颖的信息学技术，我们已经在先前被认为仅限于神经元和神经内分泌组织的胰岛上确定了先前未识别的候选标记。该数据清楚地揭示了胰岛细胞与神经和神经内分泌谱系之间的特定分子/功能重叠，从而使我们现在可以利用大量的经验和研究，这些经验和研究集中在CNS的功能成像上。根据我们在识别特定标记的努力，我们现在建议针对β细胞囊泡单胺转运蛋白，使用PET放射性数的2型（VMAT2）将提供β细胞质量和功能的定量测量。我们有三个具体的目标，旨在提供必要的临床前数据，以尽可能地通过VMAT2靶向将胰岛成像移动到临床试验中。在特定目标中，我们概述了在我们的宠物化学实验室中建立VMAT2配体的放射合成的必要步骤。具体目标两个重点是扩展我们对β细胞中2型囊泡单胺转运蛋白的超微结构和细胞生物学的理解。在特定目标三中，我们概述了旨在显示原理证明的糖尿病和胰岛移植动物模型的一系列研究（即VMAT2靶向靶向提供了对β细胞量的定量测量，可用于管理和研究人类类型1型糖尿病和胰岛移植）。我们将基本细胞生物学家，移植外科医生和核医学专家组成的跨学科研究团队汇总了开发成像试剂和技术的共同目标，这些试剂和技术将胰岛与周围环境区分开来，并提供对其质量的定量测量。