Effects of Radiation on Brain Microvasculature and Cognition

辐射对脑微血管和认知的影响

基本信息

批准号：
8013522
负责人：
William Edmund Sonntag
金额：
$ 36.96万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-15 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8013522
关键词：
Acetylcholine Adverse effects Aftercare Age Angiotensin II Angiotensin-Converting Enzyme Inhibitors Animals Anterior Anxiety Apoptosis Attenuated Blood - brain barrier anatomy Blood Vessels Blood capillaries Brain Brain Injuries Brain Neoplasms Brain region Cancer Patient Cardiovascular system Cerebrovascular Circulation Cerebrum Cognition Cognitive Cranial Irradiation Dementia Development Diagnosis Disseminated Malignant Neoplasm Doctor of Philosophy Dose EGF gene Electrolytes Endothelial Cells Etiology Functional disorder Generations Glucose Hippocampus (Brain)Homeostasis Hypoxia Impaired cognition Impairment Incidence Injury Kidney Lead Learning Liquid substance Long-Term Survivors Losartan Lung Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Measures Memory Metastatic malignant neoplasm to brain Neuroglia Neurologic Manifestations Newly Diagnosed Organ Oxidative Stress Pain Patients Perception Prevention strategy Procedures Process Protocols documentation Radiation Radiation induced damage Ramipril Rattus norvegicus Renin-Angiotensin System Research Personnel Severities Site Stress System Testing Time Treatment Efficacy Vascular Endothelial Growth Factors age related arteriole base capillary cerebrovascular cingulate cortex clinically relevant cognitive function density dentate gyrus functional disability glucose metabolism improved innovation irradiation malignant breast neoplasm melanoma middle age paracrine prevent programs radiation effect receptor response venule

项目摘要

DESCRIPTION (provided by applicant): Whole brain irradiation (WBI) leads to a progressive dementia in approximately 20-50% of brain tumor patients who are long-term survivors after treatment. At the present time, there are no successful treatments for radiation-induced brain injury, nor are there any known effective preventive strategies. We, and others, have proposed that the decline in cognitive function after WBI is exacerbated by increasing age and part of the mechanisms contributing to these impairments is a decrease in vascular density, and function of endothelial cells and the blood brain barrier. We hypothesize that fractionated WBI results in cognitive impairment by exacerbating age-related cerebrovascular rarefaction resulting in a decline in cerebral blood flow and impairments in glucose metabolism; these alterations (together with impairments in VEGF secretion) are a contributing factor in the decline in cognitive function and can be modulated by inhibition of the brain renin angiotensin system (RAS). The following aims are proposed: 1. Assess rarefaction of brain microvasculature and the corresponding decline in local cerebral blood flow (LCBF) after irradiation in brain regions specifically associated with learning and memory. 2. Determine whether trophic factors (e.g. VEGF and its receptors) produced by the vasculature and glia and found to be necessary for hippocampally- dependent processes of learning and memory are reduced in the hippocampal microenvironment of irradiated animals. 3. Assess whether irradiation results in microvascular endothelial dysfunction and disruptions in blood brain barrier integrity and whether the effects of irradiation are ameliorated by inhibition of the RAS system. 4. Determine whether administration of an ACE inhibitor (ramipril) or an AT1 receptor antagonist (losartan) (that have been shown to prevent radiation induced damage) ameliorate the radiation- induced decline in vascular density, LCBF, glucose metabolism and associated with improved cognitive status/The significance/innovation of this application is that the effects of a clinically relevant fractionated dose of WBI will be used, dependent variables will be assessed in animals of known cognitive status and studies will be conducted in middle-aged animals. These procedures will allow us to make more precise conclusions related to the etiology of cognitive impairment that occurs in response to WBI and assess the efficacy of interventions to reduce cognitive impairment after radiation.

描述（由申请人提供）：整个大脑辐照（WBI）导致大约20-50％的脑肿瘤患者是长期幸存者的脑肿瘤。目前，尚无对辐射引起的脑损伤的成功治疗，也没有任何已知的有效预防策略。我们和其他人提出，WBI后认知功能的下降因年龄的增长和部分造成这些障碍的机制而加剧，这是血管密度的下降，以及内皮细胞和血液脑屏障的功能。我们假设分离的WBI通过加剧与年龄有关的脑血管稀疏导致认知障碍，从而导致脑血流量下降和葡萄糖代谢的损害。这些改变（以及VEGF分泌的损害）是认知功能下降的一个因素，可以通过抑制脑肾素血管紧张素系统（RAS）来调节。提出了以下目的：1。评估脑微脉管系统的罕见，并在与学习和记忆有关的大脑区域受照射后局部脑血流（LCBF）的相应下降。 2.确定脉管系统和神经胶质产生的营养因子（例如VEGF及其受体）是否在辐照动物的海马微环境中降低了海马依赖性学习和记忆过程所必需的。 3。评估辐射是否导致微血管内皮功能障碍和血液脑屏障完整性的破坏以及通过抑制RAS系统改善辐射的影响。 4. Determine whether administration of an ACE inhibitor (ramipril) or an AT1 receptor antagonist (losartan) (that have been shown to prevent radiation induced damage) ameliorate the radiation- induced decline in vascular density, LCBF, glucose metabolism and associated with improved cognitive status/The significance/innovation of this application is that the effects of a clinically relevant fractionated dose of WBI will be使用的，将在已知认知状态的动物中评估因变量，并将在中年动物中进行研究。这些程序将使我们得出与对WBI响应的认知障碍病因相关的更精确的结论，并评估干预措施的疗效以减少放射后认知障碍。