权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Radiation-induced brain injury and cognitive dysfunction in aging rats

辐射引起的老年大鼠脑损伤和认知功能障碍

基本信息

批准号：
7827999
负责人：
DAVID RAY RIDDLE
金额：
$ 36万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-06 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7827999
关键词：
Acute Address Adult Affect Age-Years Aging Agonist Animal Model Animals Anti-Inflammatory Agents Binding Brain Brain Injuries Brain Neoplasms Cancer Patient Cells Chronic Clinic Clinical Clinical Treatment Cognitive Cognitive deficits Cranial Irradiation Development Dose Elderly Epidemiologic Studies Event Foundations Future Gene Expression Immune Impaired cognition Inflammation Inflammatory Inflammatory Response Injury Investigation Knowledge Long-Term Survivors Measures Mediating Mediator of activation protein Memory Microglia Modeling Molecular Nature Neoplasm Metastasis Neurobiology Neurons Oxidative Stress Pathway interactions Patients Pattern Phenotype Pioglitazone Population Primary Brain Neoplasms Proliferating Public Health Radiation Radiation-Induced Change Rattus Regimen Relative (related person)Research Risk Rodent Running Severities Testing Tissues Translating age effect aging brain autocrine brain cell brain tissue cell type clinically relevant cognitive function cytokine effective therapy executive function expectation indexing inflammatory marker killings middle age paracrine prevent public health relevance receptor relating to nervous system research study response therapy development young adult

项目摘要

DESCRIPTION (provided by applicant): Whole brain irradiation (WBI) is an effective treatment for brain tumors and metastases but 50% or more of the long-term survivors treated with WBI suffer cognitive deficits attributed to radiation-induced injury to normal brain tissue. The cellular and molecular mechanisms underlying the deficits are not well understood, but it is clear that radiation kills proliferating cells and also induces acute and chronic oxidative stress and inflammatory responses that alter the function of surviving cells. Although investigations of the mechanisms of radiation-induced brain injury in animal models have begun to reveal key pathways and mediators, translating the knowledge gained from these studies to the clinic is difficult since experimental studies of radiation-induced brain injury in adult rodents have used, almost without exception, very young adults. In contrast, in the clinical population, the majority of adult patients treated with WBI are 50 years of age or older. Since brain aging is accompanied by changes both in proliferating cell populations and in basal levels of inflammation and oxidative stress, the effects of WBI on the older brain are likely to be substantially different from the effects in young adults. This expectation is supported by our preliminary studies and by epidemiological evidence that aging increases the likelihood and the severity of radiation-induced cognitive decline. Treatment of radiation-induced cognitive dysfunction would benefit tremendously from a better understanding of the cellular and molecular responses that follow WBI, but it is critical to test radiation-induced changes in neurobiological measures and cognitive functions following a clinically relevant regimen of WBI and in animals that best model the relevant clinical population. The experiments proposed here will i) provide the first direct test of the effects of aging on radiation-induced deficits in a range of cognitive functions, ii) clarify the key cellular and molecular events that contribute to those functional changes, and iii) test whether treatment with the peroxisomal proliferator-activated receptor (PPAR)? agonist, pioglitazone, an anti-inflammatory agent, prevents radiation-induced cognitive dysfunction in old rats. The information that will be provided by this quantitative analysis of radiation-induced injury in young and old rats is critical to translational efforts to develop therapies to prevent or ameliorate radiation-induced cognitive dysfunction. In the absence of such studies, one runs the significant risk of targeting mechanisms of injury that may be of lesser significance in the primary clinical population. PUBLIC HEALTH RELEVANCE: This research is relative to public health because it will test the effects of a clinically relevant radiation treatment on the development of brain injury and cognitive deficits in an animal model that is amenable to experimental manipulation and that appropriately reflects the primary clinical population, middle age and older adults. Such studies will facilitate the development of new and more efficacious treatments to prevent or reduce radiation-induced brain injury and thereby provide benefits to cancer patients.

描述（由申请方提供）：全脑照射（WBI）是脑肿瘤和转移瘤的有效治疗方法，但接受WBI治疗的长期存活者中有50%或更多的人因辐射诱导的正常脑组织损伤而出现认知缺陷。这些缺陷背后的细胞和分子机制尚不清楚，但很明显，辐射杀死增殖细胞，还诱导急性和慢性氧化应激和炎症反应，改变存活细胞的功能。虽然在动物模型中对辐射诱发脑损伤机制的研究已开始揭示关键途径和介质，但将从这些研究中获得的知识转化为临床是困难的，因为在成年啮齿动物中进行的辐射诱发脑损伤实验研究几乎无一例外地使用了非常年轻的成年人。相比之下，在临床人群中，大多数接受WBI治疗的成人患者年龄在50岁或以上。由于脑老化伴随着增殖细胞群和炎症和氧化应激的基础水平的变化，WBI对老年人大脑的影响可能与年轻人的影响有很大不同。我们的初步研究和流行病学证据支持了这一预期，即老龄化增加了辐射引起的认知能力下降的可能性和严重性。辐射诱导的认知功能障碍的治疗将极大地受益于更好地理解WBI后的细胞和分子反应，但在临床相关的WBI方案和最佳模拟相关临床人群的动物中测试辐射诱导的神经生物学指标和认知功能变化至关重要。这里提出的实验将i）提供第一个直接测试的影响，老化辐射诱导的缺陷在一系列的认知功能，ii）澄清的关键细胞和分子事件，有助于这些功能的变化，和iii）测试是否治疗与过氧化物酶体增殖物激活受体（PPAR）？激动剂，吡格列酮，一种抗炎剂，预防老年大鼠辐射诱导的认知功能障碍。通过对年轻和老年大鼠辐射诱导损伤的定量分析所提供的信息对于开发预防或改善辐射诱导的认知功能障碍的疗法的转化努力至关重要。在缺乏此类研究的情况下，靶向损伤机制的风险很大，在主要临床人群中可能意义不大。公共卫生相关性：这项研究与公共卫生有关，因为它将测试临床相关放射治疗对动物模型中脑损伤和认知缺陷发展的影响，该模型适合实验操作，并适当反映了主要临床人群，中年和老年人。这些研究将促进开发新的和更有效的治疗方法，以预防或减少辐射引起的脑损伤，从而为癌症患者提供益处。