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略性和致命的人类肿瘤之一，通常会影响儿童和年轻人。转基因和基因靶向方法的可用性，以及大量自发性和诱导的突变小鼠菌株，导致小鼠用作研究癌症的关键动物模型系统的使用增加。在过去的几年中，小鼠遗传学的使用在理解甲状腺母细胞瘤和胶质瘤的形成和进展的遗传途径和分子事件方面已取得了重大进展，分别是最常见的儿科和成人脑肿瘤。为了实现这些基因工程小鼠模型的全部潜力，必须开发体内微观成像方法，从而可以对肿瘤进展和对新型治疗剂的反应进行纵向分析。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。该项目的广泛目标是开发功能和分子磁共振微成像（MU MRI）方法，以检测和量化小鼠脑肿瘤中的血管生成。最近，我们在子宫逆转录病毒注射中使用了肌细胞小脑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，即血管生成的量度来诱导神经胶质瘤，还将研究转基因小鼠神经胶质瘤模型。我们正在开发造影剂增强的灌注MU MRI技术，以测量正常小鼠脑和脑肿瘤中的脑血容量（CBV）方法。还将开发直接的体内分子靶向方法来评估血管生成。我们将产生转基因小鼠，该小鼠过表达新生血管内皮细胞中的细胞表面受体，并在静脉注射超帕磁性MRI对比剂标记的配体后静脉注射后这些小鼠的大脑成像。这些转基因小鼠将诱导脑肿瘤，并用MU MRI成像，以量化发育中的脑肿瘤中的血管密度。功能性和分子MU MRI方法将在探索性，可行性阶段（R21）开发，后来在开发阶段仔细研究肿瘤进展和对抗血管生成疗法的反应（R33）。在该项目下开发的新技术对于理解血管生成和脑肿瘤进展至关重要，并且将在遗传准确的癌症模型中彻底改变肿瘤生物学。