The Renin-Angiotensin System, Inflammation and Radiation-induced Brain Injury

肾素-血管紧张素系统、炎症和辐射引起的脑损伤

基本信息

批准号：
7886710
负责人：
MICHAEL E. ROBBINS
金额：
$ 24.73万
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：
2006
资助国家：
美国
起止时间：
2006-08-07 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7886710
关键词：
Acetylcholine Acute Adult Adverse effects Aftercare Age Angiotensin II Angiotensin II Receptor Angiotensin II Type 1 Receptor Blockers Angiotensin-Converting Enzyme Inhibitors Anxiety Area Astrocytes Attenuated Brain Brain Injuries Brain Neoplasms Breast Cancer Patient Cerebrum Chronic Clinic Cognition Cognitive Cranial Irradiation Data Dementia Development Diagnosis Disseminated Malignant Neoplasm Endothelial Cells Hour Impaired cognition In Vitro Inbred F344 Rats Incidence Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Kidney Late Effects Lead Long-Term Survivors Lung Malignant Neoplasms Malignant neoplasm of prostate Memory Metastatic malignant neoplasm to brain Microglia Modeling NADPH Oxidase Neurologic Manifestations Newly Diagnosed Organ Oxidases Oxidative Stress Pain Patients Perception Performance Phenotype Prevention strategy Public Health Quality of life Radiation Radiation-Induced Change Ramipril Rattus Regimen Renin-Angiotensin System Research Personnel Rodent Role Severities Signal Pathway Signal Transduction Site Stress Testing Therapeutic Time Translations Tretinoin Up-Regulation age related base brain cell cancer therapy clinically relevant cognitive function human subject improved in vitro Model in vivo male prevent programs receptor transcription factor

项目摘要

DESCRIPTION (provided by applicant): The NCI has identified long-term survival from cancer as one of the new areas of public health emphasis; the late effects of cancer treatments are of particular importance. Progressive dementia occurs in some 20-50% of brain tumor patients who are long-term survivors after treatment with brain irradiation. The need to both understand and minimize the side effects of brain irradiation is exacerbated by the ever- increasing number of patients with brain metastases that require treatment with large field or whole brain irradiation (WBI); some 200,000 cancer patients/year receive large field or WBI. At the present time, there are no successful treatments for radiation-induced brain injury, nor are there any known effective preventive strategies. Data support a role for the renin-angiotensin system (RAS) in radiation-induced late effects in kidney, lung; both angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II (Ang II) receptor antagonists (ATRA) have proved effective. However, the pathogenic mechanism(s) involved remains unknown. Recent studies have identified a functioning RAS in the brain that is involved in cognition, memory, anxiety and stress. We hypothesize that WBI upregulated the intrinsic brain RAS, leading to a chronic and persistent oxidative stress/inflammatory response that results in the development and progression of radiation-induced brain injury, including cognitive impairment. To test this hypothesis we will pursue the following in vitro and in vivo Specific Aims: In Aims 1 and 2 we will test the hypothesis that inhibiting Ang II in normal brain cells will reduce the severity of pro-inflammatory changes in brain cell phenotype and/or function. We will use well-defined models of primary rat astrocytes, rat brain microvascular endothelial cells and rat microglia. In aims 3 and 4 we will test the hypothesis that inhibiting the intrinsic brain RAS using RAS blockers targeted at either ACE (ACEI), or the Ang II receptors (AT1RA and AT2RA) will ameliorate the development and progression of radiation-induced brain injury in vivo. Rats will receive a clinically relevant fractionated course of WBI, and acute (Specific Aim 3) and chronic (Specific Aim 4) changes in components of the RAS and pro-inflammatory mediators will be determined, as well as chronic changes in cognitive function. The establishment of an interventional role for Ang II blockers in modulating radiation-induced brain injury should lead to the rapid translation of these findings to the clinic, with the promise of increasing the therapeutic window for cancer patients receiving large field or WBI as well as improving their quality of life.

描述（由申请人提供）：NCI 已将癌症长期生存确定为公共卫生重点的新领域之一；癌症治疗的后期影响尤为重要。接受脑部照射治疗后长期存活的脑肿瘤患者中，约 20-50% 会出现进行性痴呆。由于需要大视野或全脑照射（WBI）治疗的脑转移患者数量不断增加，因此更加需要了解并尽量减少脑照射的副作用；每年约有 200,000 名癌症患者接受大视野或 WBI。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。数据支持肾素-血管紧张素系统 (RAS) 在辐射引起的肾、肺迟发效应中发挥作用；血管紧张素转换酶抑制剂（ACEI）和血管紧张素II（Ang II）受体拮抗剂（ATRA）均已被证明有效。然而，所涉及的致病机制仍然未知。最近的研究发现大脑中的 RAS 功能正常，与认知、记忆、焦虑和压力有关。我们假设 WBI 上调了大脑内在 RAS，导致慢性持续的氧化应激/炎症反应，导致辐射引起的脑损伤（包括认知障碍）的发生和进展。为了检验这一假设，我们将追求以下体外和体内具体目标：在目标 1 和 2 中，我们将检验以下假设：抑制正常脑细胞中的 Ang II 将降低脑细胞表型和/或促炎症变化的严重程度。或函数。我们将使用明确的原代大鼠星形胶质细胞、大鼠脑微血管内皮细胞和大鼠小胶质细胞模型。在目标 3 和 4 中，我们将检验以下假设：使用针对 ACE (ACEI) 或 Ang II 受体（AT1RA 和 AT2RA）的 RAS 阻滞剂抑制内在脑 RAS 将改善辐射诱发的脑损伤的发生和进展。体内。大鼠将接受临床相关的 WBI 分次疗程，并确定 RAS 成分和促炎介质的急性（具体目标 3）和慢性（具体目标 4）变化，以及认知功能的慢性变化。 Ang II 阻滞剂在调节辐射引起的脑损伤中的介入作用的建立应该会导致这些发现迅速转化为临床，有望增加接受大视野或 WBI 的癌症患者的治疗窗口，并改善他们的生活质量。