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: 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
• 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

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；癌症治疗的后期作用尤其重要。在大约20-50％的脑肿瘤患者中，脑部肿瘤患者是长期幸存者。不断增加的脑转移患者数量不断增加，需要大脑转移的患者数量不断增加，这些患者需要大脑或整个脑照射（WBI），这一需求使大脑照射的副作用加剧了。大约20万名癌症患者/年接受大型野外或WBI。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。数据支持肾素 - 血管紧张素系统（RAS）在辐射诱导的肾脏后期作用中的作用；证明血管紧张素转化酶抑制剂（ACEI）和血管紧张素II（ANG II）受体拮抗剂（ATRA）均已证明有效。但是，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功能性RA，与认知，记忆，焦虑和压力有关。我们假设WBI上调了内在的脑RA，导致慢性和持续的氧化应激/炎症反应导致辐射引起的脑损伤的发展和进展，包括认知障碍。为了检验该假设，我们将在体外和体内特定目的进行以下以下目的：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将减少脑细胞表型和/或功能中促炎性变化的严重性。我们将使用定义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的模型。在目标3和4中，我们将测试以下假设：使用靶向ACE（ACEI）的RAS阻滞剂抑制固有的脑RAS，或者ANG II受体（AT1RA和AT2RA）将改善体内辐射诱导的脑损伤的发展和进展。将确定大鼠在WBI的临床上分馏过程，急性（特定目标3）和RAS组成部分的慢性（特定目标4）变化将确定和促炎性介体的成分，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方面的介入作用应导致这些发现的快速转化给诊所，并有望增加接受大型野外或WBI的癌症患者的治疗窗口，并提高其生活质量。