NMR Studies of the Induction of Cerebral Angiogenesis

描述（由申请人提供）： 血管生成是脑组织对缺氧和缺血的天然防御机制的一部分。该提案将解决稳态NMR成像将检测血管生成诱导的脑血容量（CBV）变化的假设。治疗性血管生成在心肌缺血和外周血管疾病中正在研究中，但刺激血管生成以改善脑缺血预后的潜力尚不清楚。阐明血管生成和消退的时间过程将有助于血管生成干预措施的研究。在这个模型中生长因子表达的时间过程是已知的，但这项工作将提供分子生物学变化和形态学反应之间的联系。一种非侵入性的，可重复的方法来研究脑血管生成将被开发和应用于在同一动物中进行多次测量。这是使用基于血清的造影剂（MION）的稳态NMR成像方法。通过量化单晶氧化铁纳米颗粒（MION）输注前后的弛豫速率R2，我们将获得脑微血管体积的指数。适应低压缺氧会增加微血管密度。我们将通过显示CBV的NMR测量与脑血管生成相关来验证成像方法。然后将在血管生成和消退的时间过程中在相同动物中测量CBV。最后，初步研究将确定是否可以用我们的技术诱导和检测使用HIF-1 α的氧稳定构建体（其上调诱导VEGF，一种有效的血管生成刺激物）的腺病毒转染的血管生成。

DESCRIPTION (provided by applicant): Angiogenesis is part of the natural defense mechanism in brain against hypoxia and ischemia. This proposal will address the hypothesis that steady state NMR imaging will detect changes in cerebral blood volume (CBV) induced by angiogenesis. Therapeutic angiogenesis is being investigated in myocardial ischemia and peripheral vascular disease, but the potential of stimulating angiogenesis to improve outcome in cerebral ischemia is unknown. Elucidating the time course of angiogenesis and regression will facilitate the study of angiogenic interventions. The time course of growth factor expression in this model is known, but this work will provide a link between molecular biological changes and morphological responses. A non-invasive, repeatable method for studying angiogenesis in brain will be developed and applied for making multiple measurements in the same animals. This is a steady state NMR imaging method using a serum based contrast agent (MION). By quantifying the relaxation rate R2 before and after infusion of monocrystalline iron-oxide nanoparticles (MION), we will obtain an index of cerebral microvascular volume. Adaptation to hypobaric hypoxia will increase microvessel density. We will validate the imaging method by showing that that the NMR measurements of CBV correlate with cerebral angiogenesis. CBV will then be measured in the same animals over a time course of angiogenesis and regression. Finally, a pilot study will determine if angiogenesis using adenoviral transfection of an oxygen-stable construct of HIF-la (the upregulation of which induces VEGF, a potent angiogenic stimulus) can be induced and detected with our technique.