Pulmonary Transgene Expression Imaging with PET

使用 PET 进行肺部转基因表达成像

基本信息

批准号：
7150604
负责人：
Daniel P Schuster
金额：
$ 44.49万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-15 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7150604
关键词：
Acute Acute Lung Injury Address Adenovirus Vector Adrenergic Receptor Adult Adult Respiratory Distress Syndrome Affect Animal Model Animals Biology Clinical Trials Data Disease Disease Outcome Disease model Dose Echocardiography Epoprostenol Experimental Animal Model Experimental Models Foundations Functional disorder Gene Expression Gene Expression Profiling Gene-Modified Genes Genetic Materials Herpesvirus 1 Human Image Imaging Techniques Invasive Label Location Lung Measures Methods Modeling Monitor Monocrotaline Organism Physiological Positron Positron-Emission Tomography Procedures Process Prostaglandins Protocols documentation Pulmonary Hypertension Rattus Reporter Reporter Genes Research Research Design Right Ventricular Hypertrophy Rodent Scientist Series Techniques Therapeutic Thymidine Kinase Time Tissue Sample Transgenes Translating Translations Variant Vascular Diseases Viral Viral Physiology Viral Vector Week base beta-2 Adrenergic Receptors disease natural history human disease in vitro Assay in vivo lung injury molecular imaging mutant primary pulmonary hypertension progesterone 11-hemisuccinate-(2-iodohistamine)promoter response therapeutic transgene transgene expression vector

项目摘要

DESCRIPTION (provided by applicant): Although it is already clear that positron emission tomographic (PET) imaging can be used to follow transgene expression in whole animals, no studies to date have yet demonstrated the utility of using molecular imaging methods, such as PET, to follow transgene expression in experimental models of disease. We propose to address this important issue by administering, to rats, adenoviral vectors carrying biologically relevant genes (shown previously by collaborators to affect the pathophysiology of different disease models of the acute respiratory distress syndrome, ARDS, and of pulmonary hypertension) and a "PET reporter gene" (e.g. viral thymidine kinase, tk), both under the control of the same promoter. Imaging will be performed to follow the location (within the lungs), timing (onset and duration), and magnitude of reporter transgene expression in relation to the physiologic effects (also studied with non-invasive imaging) of the disease modifying genes. Thus, our proposal has the following specific aims: Specific Aim 1: using PET imaging, determine the timing, magnitude, duration, and functional effects of beta-2 adrenergic receptor (beta2AR) transgene expression during experimental lung injury. 1.a Measure changes with PET and in vitro assays of beta2AR and tk expression as a function of viral dose. 1.b Determine the time course of gene expression with PET in normal animals. 1.c Correlate (temporally and geographically, i.e. within the lungs) PET reporter gene expression, beta-2 adrenergic receptor transgene expression, and functional effects of the beta2AR transgene (also evaluated with PET imaging) in acute hyperoxic lung injury (a lung injury model of ARDS). Specific Aim 2: using PET imaging and echocardiography, determine the timing, magnitude, duration, and functional effects of prostaglandin I2 synthase transgene expression during experimental pulmonary hypertension. An analogous series of studies (Specific Aims 2.a, 2.b and 2.c) will be implemented in two variants of the monocrotaline model of pulmonary hypertension, a model of sub-acute pulmonary vascular disease. The results will demonstrate how PET imaging can be used to study the impact of changes in gene expression on the natural history of disease or to develop therapeutic protocols to alter disease outcome.

描述（由申请人提供）：尽管已经很明显，正电子发射断层扫描（PET）成像可用于跟随整个动物的转基因表达，但迄今为止，尚无研究表明使用分子成像方法（例如PET）在疾病实验模型中遵循转基因表达的实用性。 We propose to address this important issue by administering, to rats, adenoviral vectors carrying biologically relevant genes (shown previously by collaborators to affect the pathophysiology of different disease models of the acute respiratory distress syndrome, ARDS, and of pulmonary hypertension) and a "PET reporter gene" (e.g. viral thymidine kinase, tk), both under the control of the same promoter.将进行成像，以遵循与疾病修饰基因的生理效应（也用非侵入性成像研究）有关的位置（肺部内），时机（发作和持续时间）以及报告基因转基因表达的大小。因此，我们的建议具有以下特定目的：特定目标1：使用PET成像，确定β-2肾上腺素能受体（BETA2AR）转基因在实验性肺损伤过程中的时机，大小，持续时间和功能效应。 1.衡量PET的变化和beta2AR和TK表达的体外测定与病毒剂量的关系。 1.b确定正常动物中PET的基因表达的时间过程。 1.C相关（在时间和地理上，即在肺部内）宠物报道基因表达，β-2肾上腺素能受体转基因表达和β2AR转基因（也通过PET成像评估）在急性高氧化肺损伤中的功能效应（ARDS的肺损伤模型）。具体目标2：使用PET成像和超声心动图，确定前列腺素I2合酶转基因表达在实验性肺动脉高压期间的时间，大小，持续时间和功能效应。一系列类似的研究（特定目标2.a，2.b和2.c）将在肺动脉高压的单蛋白模型的两个变体中实施，肺动脉高压是亚急性肺血管疾病的模型。结果将证明如何使用PET成像来研究基因表达变化对疾病自然史的影响或开发治疗方案以改变疾病预后。