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

• 批准号: 7485698
• 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
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-07 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7485698
• 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; Inflammatory; Inflammatory Response; Injury; Kidney; L 158809; Late Effects; Lead; Long-Term Survivors; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Mediator of activation protein; Memory; Metastatic malignant neoplasm to brain; Microglia; Modeling; NADPH Oxidase; Neurologic Manifestations; Newly Diagnosed; Numbers; Organ; Oxidases; Oxidative Stress; PD 123319; Pain; Patients; Perception; Performance; Phenotype; Prevention strategy; Public Health; Quality of life; Radiation; Radiation-Induced Change; Ramipril; Rattus; Renin-Angiotensin System; Research Personnel; Rodent; Role; Severities; Signal Pathway; Signal Transduction; Site; Stress; Testing; Therapeutic; Time; Translations; Treatment Protocols; Tretinoin; Up-Regulation; age related; base; brain cell; cancer therapy; clinically relevant; cognitive function; day; human subject; improved; in vitro Model; in vivo; male; prevent; programs; receptor; transcription factor

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已将癌症的长期生存确定为公共卫生重点的新领域之一;癌症治疗的晚期效应特别重要。进行性痴呆发生在大约20-50%的脑肿瘤患者中，这些患者是脑放射治疗后的长期幸存者。需要理解和最小化脑照射的副作用的需要由于需要用大视野或全脑照射（WBI）治疗的脑转移患者的数量不断增加而加剧;每年约200，000名癌症患者接受大视野或WBI。目前，还没有成功的治疗放射性脑损伤的方法，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）在肾、肺辐射诱导的迟发效应中的作用;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）已被证明有效。然而，涉及的致病机制仍然未知。最近的研究已经确定了大脑中的一个功能RAS，它涉及认知，记忆，焦虑和压力。我们假设WBI上调了内在的脑RAS，导致慢性和持续的氧化应激/炎症反应，导致辐射诱导的脑损伤（包括认知障碍）的发展和进展。为了检验这一假设，我们将追求以下体外和体内特定目的：在目的1和2中，我们将检验抑制正常脑细胞中的Ang II将降低脑细胞表型和/或功能中促炎性变化的严重性的假设。我们将使用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的明确模型。在目标3和4中，我们将测试使用靶向ACE（ACEI）或Ang II受体（AT 1 RA和AT 2 RA）的RAS阻断剂抑制内在脑RAS将改善体内辐射诱导的脑损伤的发展和进展的假设。大鼠将接受临床相关的WBI分次疗程，并确定RAS和促炎介质组分的急性（特定目标3）和慢性（特定目标4）变化以及认知功能的慢性变化。血管紧张素II受体阻滞剂在调节放射性脑损伤中的干预作用的建立，应导致这些研究结果的快速翻译到临床，增加癌症患者接受大视野或WBI的治疗窗口，以及改善他们的生活质量的承诺。