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）：全脑照射 (WBI) 会导致约 20-50% 治疗后长期存活的脑肿瘤患者出现进行性痴呆。目前，对于放射性脑损伤还没有成功的治疗方法，也没有任何已知的有效预防策略。我们和其他人提出，WBI 后认知功能的下降会因年龄的增长而加剧，导致这些损害的部分机制是血管密度、内皮细胞和血脑屏障功能的下降。我们假设分次 WBI 会加剧与年龄相关的脑血管稀疏，从而导致脑血流量减少和葡萄糖代谢受损，从而导致认知障碍；这些改变（连同 VEGF 分泌受损）是认知功能下降的一个促成因素，可以通过抑制脑肾素血管紧张素系统 (RAS) 来调节。提出以下目标： 1. 评估与学习和记忆特别相关的大脑区域照射后大脑微血管的稀疏和局部脑血流量 (LCBF) 的相应下降。 2. 确定在受辐射动物的海马微环境中，脉管系统和神经胶质细胞产生的、海马依赖性学习和记忆过程所必需的营养因子（例如 VEGF 及其受体）是否减少。 3. 评估辐射是否会导致微血管内皮功能障碍和血脑屏障完整性破坏，以及是否可以通过抑制 RAS 系统来改善辐射的影响。 4. 确定使用 ACE 抑制剂（雷米普利）或 AT1 受体拮抗剂（氯沙坦）（已被证明可以预防辐射引起的损伤）是否可以改善辐射引起的血管密度、LCBF、葡萄糖代谢下降，并与改善认知能力相关状态/本申请的意义/创新在于，将使用临床相关分次剂量的WBI的效果，将在已知认知状态的动物中评估因变量，并在中年动物中进行研究。这些程序将使我们能够对 WBI 引起的认知障碍的病因学做出更准确的结论，并评估减少放射后认知障碍的干预措施的有效性。