In vivo studies of cerebral angiogenesis and oxygenation

脑血管生成和氧合的体内研究

• 批准号: 6949665
• 负责人: Jeffrey Frank Dunn
• 金额: $ 19.51万
• 依托单位: UNIVERSITY OF CALGARY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-20 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6949665
• 关键词: Adenoviridae; angiogenesis; blood volume; brain circulation; cerebral ischemia /hypoxia; electron spin resonance spectroscopy; gene expression; gene therapy; hypoxia inducible factor 1; immunocytochemistry; infrared spectrometry; laboratory rat; longitudinal animal study; molecular biology; morphology; morphometry; nonhuman therapy evaluation; nuclear magnetic resonance spectroscopy; oxygen transport; protein biosynthesis; respiratory oxygenation; therapy design /development; transfection; transfection /expression vector

DESCRIPTION (provided by applicant): There are many clinical conditions where the brain may be damaged from chronic hypoxia including ischemia, pulmonary disorders, SIDS, anemia, dialysis, high altitude cerebral edema and Parkinson's disease. If chronic hypoxia does cause brain damage, it follows that the adaptation of the brain to chronic hypoxia is incomplete, and may be improved through induction of angiogenesis. Recent work indicates that the brain is capable of adaptation to low oxygen through angiogenesis. There is strong evidence that HIF-1alpha is a major regulatory factor in this process. We have assembled a multidisciplinary program using our unique combination of tools (including molecular biological methods, near-infrared spectroscopy, NMR and electron paramagnetic resonance) to determine the impact of tissue hypoxia on HIF-1alpha in normal and ischemic brain, and to determine the temporal link between the upregulation of HIF-1alpha and changes in brain tissue oxygenation and angiogenesis. Cerebral oxygenation is defined as the mean cerebral hemoglobin saturation (SmcO2) measured using near-infrared (NIR) spectroscopy, and the tissue pO2 (PtO2) measured using electron paramagnetic resonance (EPR) spectroscopy. In Aim 1 we study the link between HIF-1alpha stabilization and PtO2. Aim 2 will study the response of the brain to chronic hypoxia, and to the re-supply of oxygen. This includes the time-course of increased and decreased HIF-1alpha, the time-course of angiogenesis and angioregression (measured using morphometrics and cerebral blood volume where CBV is measured with quantitative NIR spectroscopy and with steady-state contrast enhanced NMR imaging), and the changes in oxygenation. Aim 3 following a similar protocol, will study chronic low flow ischemia. We will determine if HIF-1alpha is upregulated, the time-course of angiogenesis, and whether cerebral oxygenation shows complete recovery. Aim 4 will determine if the Genzyme adenovirus, containing a non-oxygen responsive HIF-1alpha construct, will result in increased HIF-1alpha protein and increased vascular density. These studies will improve our understanding of the link between angiogenesis, HIF-1alpha upregulation and oxygenation in brain, and will lay the groundwork for manipulation of angiogenesis to improve outcome from chronic hypoxia or ischemia.

描述（由申请人提供）：有许多临床病症可能因慢性缺氧而导致大脑受损，包括缺血、肺部疾病、SIDS、贫血、透析、高海拔脑水肿和帕金森病。如果慢性缺氧确实导致脑损伤，那么脑对慢性缺氧的适应是不完全的，并且可以通过诱导血管生成来改善。最近的研究表明，大脑能够通过血管生成来适应低氧。有强有力的证据表明，HIF-1 α是这一过程中的主要调节因子。我们已经组装了一个多学科的程序，使用我们独特的工具组合（包括分子生物学方法，近红外光谱，核磁共振和电子顺磁共振），以确定组织缺氧对正常和缺血性脑组织中HIF-1 α的影响，并确定HIF-1 α的上调与脑组织氧合和血管生成变化之间的时间联系。脑氧合定义为使用近红外（NIR）光谱测量的平均脑血红蛋白饱和度（SmcO 2）和使用电子顺磁共振（EPR）光谱测量的组织pO 2（PtO 2）。在目标1中，我们研究了HIF-1 α稳定性和PtO 2之间的联系。目的2将研究大脑对慢性缺氧的反应，以及对氧气再供应的反应。这包括HIF-1 α增加和减少的时间过程，血管生成和血管消退的时间过程（使用形态测量学和脑血容量测量，其中CBV用定量NIR光谱和稳态对比增强NMR成像测量），以及氧合的变化。目标3：按照类似的方案，研究慢性低血流缺血。我们将确定HIF-1 α是否上调，血管生成的时间进程，以及脑氧合是否显示完全恢复。目的4将确定是否Genzyme腺病毒，含有非氧响应HIF-1 α结构，将导致增加HIF-1 α蛋白和增加血管密度。这些研究将提高我们对血管生成、HIF-1 α上调和脑内氧合之间联系的理解，并将为操纵血管生成以改善慢性缺氧或缺血的结果奠定基础。