Functional and Molecular MRI of Mouse Brain Tumors

小鼠脑肿瘤的功能和分子 MRI

• 批准号: 6578494
• 负责人: Daniel H Turnbull
• 金额: $ 16.88万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6578494
• 关键词: Retroviridae; angiogenesis; bioimaging /biomedical imaging; brain circulation; brain imaging /visualization /scanning; brain neoplasms; diagnosis design /evaluation; disease /disorder model; genetically modified animals; glioma; laboratory mouse; longitudinal animal study; magnetic resonance imaging; medulloblastoma; neoplasm /cancer blood supply; neoplasm /cancer diagnosis; neoplastic process; receptor expression; transferrin receptor; viral carcinogenesis

DESCRIPTION (provided by applicant): Primary brain tumors are among the most aggressive and fatal human neoplasms, often affecting children and younger adults. The availability of transgenic and gene targeting methods, and the large number of spontaneous and induced mutant mouse strains, have led to the increased use of the mouse as a key animal model system to study cancer. In the past several years, the use of mouse genetics has led to significant progress in understanding the genetic pathways and molecular events involved in the formation and progression of both medulloblastoma and glioma, the most common pediatric and adult brain tumors, respectively. In order to realize the full potential of these genetically engineered mouse models, it is imperative to develop in vivo microscopic imaging approaches, allowing longitudinal analysis of tumor progression and response to novel therapeutic agents. Angiogenesis is thought to be a critical prerequisite for tumor progression, and brain tumor malignancy is intimately related to angiogenesis and vascular density, especially in gliomas. The broad goals of this project are to develop both functional and molecular magnetic resonance micro-imaging (mu MRI) approaches to detect and quantify angiogenesis in mouse brain tumors. We have recently used in utero retrovirus injection to induce medulloblastomas in the postnatal mouse cerebellum. We propose to use a similar retrovirus injection, a measure of angiogenesis to induce gliomas, and will also investigate a transgenic mouse glioma model. We are developing contrast-enhanced perfusion mu MRI techniques to measure cerebral blood volume (CBV) approach in normal mouse brain and brain tumors. A direct, in vivo molecular targeting approach will also be developed to assess angiogenesis. We will generate transgenic mice that overexpress cell surface receptors in neovascular endothelial cells, and image the brains of these mice after intravenous injection of a superparamagnetic MRI contrast agent-tagged ligand. Brain tumors will be induced in these transgenic mice and imaged with mu MRI to quantify vascular density in the developing brain tumors. The functional and molecular mu MRI approaches will be developed during an exploratory, feasibility phase (R21) and later used in careful studies of tumor progression and response to anti-angiogenic therapies in a development phase (R33). The new technologies developed under this project are of critical importance for understanding angiogenesis and brain tumor progression, and will revolutionize tumor biology in genetically accurate mouse models of cancer.

描述（由申请人提供）：原发性脑肿瘤是最具侵袭性和致命性的人类肿瘤之一，通常影响儿童和年轻人。转基因和基因靶向方法的可用性，以及大量自发和诱导突变小鼠品系，导致越来越多地使用小鼠作为研究癌症的关键动物模型系统。在过去的几年中，小鼠遗传学的应用在了解髓母细胞瘤和神经胶质瘤（分别是最常见的儿童和成人脑肿瘤）形成和进展所涉及的遗传途径和分子事件方面取得了重大进展。为了充分发挥这些基因工程小鼠模型的潜力，必须开发体内显微成像方法，从而能够纵向分析肿瘤进展和对新型治疗药物的反应。血管生成被认为是肿瘤进展的关键先决条件，脑肿瘤恶性肿瘤与血管生成和血管密度密切相关，尤其是在神经胶质瘤中。该项目的总体目标是开发功能性和分子磁共振显微成像 (mu MRI) 方法来检测和量化小鼠脑肿瘤中的血管生成。我们最近使用子宫逆转录病毒注射来诱导出生后小鼠小脑中的髓母细胞瘤。我们建议使用类似的逆转录病毒注射（一种测量血管生成的方法来诱导神经胶质瘤），并且还将研究转基因小鼠神经胶质瘤模型。我们正在开发对比增强灌注 mu MRI 技术，以测量正常小鼠大脑和脑肿瘤的脑血容量 (CBV) 方法。还将开发一种直接的体内分子靶向方法来评估血管生成。我们将培育出在新生血管内皮细胞中过度表达细胞表面受体的转基因小鼠，并在静脉注射超顺磁性 MRI 造影剂标记配体后对这些小鼠的大脑进行成像。将在这些转基因小鼠中诱导脑肿瘤，并使用 mu MRI 进行成像，以量化正在发育的脑肿瘤中的血管密度。功能和分子 mu MRI 方法将在探索性可行性阶段 (R21) 进行开发，随后在开发阶段 (R33) 用于仔细研究肿瘤进展和抗血管生成疗法的反应。该项目开发的新技术对于理解血管生成和脑肿瘤进展至关重要，并将彻底改变基因精确的小鼠癌症模型中的肿瘤生物学。