PPARs and Radiation-induced Brain Injury

描述(申请人提供)：最近的数据表明，在接受脑部放射治疗后长期存活的脑肿瘤患者中，约有20%-50%会发生进行性痴呆。越来越多的继发性脑转移患者需要接受大面积或全脑照射(WBI)治疗；每年约有175,000名癌症患者接受大面积或全脑照射(WBI)治疗，这加剧了了解并尽量减少脑照射副作用的必要性。目前，还没有成功的治疗放射性脑损伤的方法，或者是否有任何已知的有效的预防策略。数据支持急性和慢性炎症和/或氧化应激在放射性脑损伤中的作用。过氧化体增殖物激活受体(PPAR)是配体激活的转录因子核激素受体超家族成员。越来越多的证据表明，PPAR激动剂在中枢神经系统具有抗炎/保护作用。 我们假设PPARpha和/或PPARGamma的激活将改善放射性脑损伤的发展和进展，包括认知障碍。为了验证这一假设，我们将追求以下具体目标。利用成熟的大鼠星形胶质细胞和大鼠脑微血管内皮细胞(RBMECs)体外模型，我们将确定：1)在辐射或其他活性氧基(ROS)处理之前，与PPARpha和/或PPARGamma激动剂预先孵育正常脑细胞是否可以抑制促炎反应和上调氧化还原调节基因产物的表达；2)使用药理抑制剂和基因转移手段抑制和增强PPARpha和PPARGamma的激活将分别防止和加强辐射及其他ROS产生刺激下观察到的PPAR对大鼠星形胶质细胞和RBMEC表型的调节。我们将通过追求以下特定目标来测试这些体外观察的体内意义：1)我们将确定长期给予PPARpha或PPARGamma激动剂是否会降低辐射诱导的脑损伤的严重程度，包括认知功能障碍；2)我们将使用PPARpha KO小鼠和条件性PPARGamma KO小鼠，在这些小鼠中，PPARGamma基因的表达将在星形胶质细胞或内皮细胞中被敲除，以检验敲除PPARpha或PPARGamma会导致放射性脑损伤增加的假设。PPAR在放射性脑损伤中致病作用的确立有望增加接受脑照射的癌症患者的治疗窗口，并对他们的生活质量和长期生存产生积极影响。

DESCRIPTION (provided by applicant): Recent data suggest that 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 secondary brain metastases that require treatment with large field or whole brain irradiation (WBI); some 175,000-cancer patients/year receive large field or WBI. At the present time, there are no successful treatments for radiation-induced brain injury, or are there any known effective preventive strategies. Data support a role for acute and chronic inflammation and/or oxidative stress in radiation-induced brain injury. Peroxisomal proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. A growing body of evidence suggests an anti-inflammatory/ protective role for PPAR agonists in the CNS. We hypothesize that activation of PPARalpha and/or PPARgamma will ameliorate the development and progression of radiation-induced brain injury, including cognitive impairment. To test this hypothesis, we will pursue the following Specific Aims. Using well-defined in vitro models of rat astrocytes and rat brain microvascular endothelial cells (RBMECs), we will determine if: 1] pre-incubating normal brain cells with PPARalpha and/or PPARgamma agonists prior to treatment with radiation or other reactive oxygen species (ROS) can inhibit the pro-inflammatory response and upregulation of redox-regulated gene products; 2] inhibiting and enhancing PPARalpha and PPARgamma activation using pharmacological inhibitors and gene-transfer approaches will prevent and enhance, respectively, the PPAR-induced modulation of rat astrocyte and RBMEC phenotype observed following treatment with radiation and other ROS generating stimuli. We will test the in vivo significance of these in vitro observations by pursuing the following Specific Aims: 1] we will determine if chronic administration of PPARalpha or PPARgamma agonists will reduce the severity of radiation-induced brain injury, including cognitive dysfunction; 2] we will use PPARalpha KO mice, and conditional PPARgamma KO mice in which PPARgamma expression will be knocked out either in astrocytes or in endothelial cells, to test the hypothesis that knocking out PPARalpha or PPARgamma will lead to increased radiation-induced brain injury. Establishment of a pathogenic role for PPARs in radiation-induced brain injury offers the promise of increasing the therapeutic window for cancer patients receiving brain irradiation and positively impacting both their quality of life and long-term survival.