PPARs and Radiation-induced Brain Injury

PPAR 和辐射引起的脑损伤

基本信息

批准号：
7909241
负责人：
MICHAEL E. ROBBINS
金额：
$ 9.99万
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：
2009-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7909241
关键词：
Adult Aftercare Agonist Anti-Inflammatory Agents Anti-inflammatory Brain Brain Injuries Brain Neoplasms Cancer Patient Cancer Survivor Cells Clinic Clinical Trials Clinical Trials Design Cranial Irradiation Development Exhibits Fenofibrate Foundations Funding Glioma Healthcare Hippocampus (Brain)Human Impaired cognition Incubated Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Intervention Ionizing radiation Late Effects Lead Ligands Long-Term Survivors Mediator of activation protein Microglia Modeling Mus Neuroglia Neurons Nuclear Hormone Receptors Oxidative Stress Patients Peroxisome Proliferator-Activated Receptors Phenotype Pioglitazone Play Population Prevention strategy Quality of life Radiation Radiation-Induced Change Rattus Risk Role Signal Pathway Testing Therapeutic Time Translating Translations Up-Regulation activating transcription factor base brain cell cancer therapy cell killing glioma cell line in vivo knock-down male member neurogenesis neuroprotection pre-clinical prevent public health relevance receptor tissue culture tumor tumor growth young adult

项目摘要

DESCRIPTION (provided by applicant): Progressive cognitive impairment occurs in up to 50% of primary and metastatic brain tumor patients who survive 6 months or longer after treatment with partial or whole-brain irradiation (WBI); ~200,000 patients/year receive these treatments. A growing body of evidence suggests that oxidative stress and pro-inflammatory responses play a critical role in radiation-induced brain injury. These observations provide the rationale for investigating anti-inflammatory-based therapeutic approaches to ameliorate or prevent radiation-induced brain injury. This competitive renewal will focus on the role of the peroxisomal proliferator-activated receptors 1 and 4 (PPAR1, PPAR4) in ameliorating or preventing radiation-induced brain injury, including cognitive impairment. These PPARs are potent mediators of anti-inflammatory responses. During the current funding period, we have demonstrated that i) administration of the PPAR3 agonist, pioglitazone, prevents fractionated WBI- induced cognitive impairment in young adult male rats; ii) the irradiated brains of PPAR1 KO mice have increased microglial activation, iii] administration of the PPAR1 agonist, fenofibrate, prevents both WBI-induced microglial activation and decreased neurogenesis, and iii) pre-treatment of microglial cells with PPAR1 agonists prevents radiation-induced increases in inflammation. In this competitive renewal, we propose to extend our PPAR1 studies and initiate studies on PPAR4, increasingly recognized as a promising pharmacological target for neuroprotection. We hypothesize that administration of PPAR1 and/or PPAR4 agonists will not only ameliorate or prevent radiation-induced brain injury, including cognitive impairment, but will also inhibit brain tumor growth. To test this hypothesis, we will pursue the following Specific Aims: 1] using a fractionated WBI rat model, we will determine if administration of PPAR1 or PPAR4 agonists will ameliorate or prevent radiation-induced brain injury, including cognitive impairment; 2] using PPAR4 KO mice, we will determine if i] knocking down PPAR4 will increase radiation-induced brain injury, and ii] if administering a PPAR4 agonist will ameliorate or prevent radiation-induced brain injury through PPAR4- dependent mechanisms; 3] using murine hippocampal neurons and microglial cells, we will determine if incubating these cells with PPAR4 agonists modulates radiation-induced changes in cellular phenotype via inhibition of pro-inflammatory signaling pathways and/or upregulation of anti-inflammatory mediators; and 4] using human glioma cell lines and immortalized normal glial cells, we will determine if treating with PPAR1 or PPAR4 agonists leads to selective glioma cell kill. Further, we will use an in vivo orthotopic rat model to determine if administering PPAR1 or PPAR4 agonists, alone or in combination with ionizing radiation, inhibits tumor growth and increases survival times. Successful completion of these aims will serve as the foundation for translating these findings into clinical trials designed to enhance the quality of life and long-term survival of cancer patients receiving partial or WBI. PUBLIC HEALTH RELEVANCE: Approximately 100,000 cancer patients per year survive long enough after partial or WBI to develop radiation- induced injury, including cognitive impairment. No successful long-term treatments for radiation-induced brain injury are currently available nor are there any effective preventive strategies. The establishment of an interventional role for PPAR1 and/or PPAR4 in radiation-induced brain injury should lead to the rapid translation of these preclinical findings to the clinic, thereby, increasing the therapeutic window for cancer patients receiving partial or WBI as well as impacting both on their quality of life and their long-term survival.

描述（由申请人提供）：逐渐认知障碍发生在多达50％的原发性和转移性脑肿瘤患者中，这些患者患有部分或全脑照射治疗后6个月或更长时间（WBI）；〜2万名患者/年接受这些治疗。越来越多的证据表明，氧化应激和促炎反应在辐射引起的脑损伤中起关键作用。这些观察结果为研究基于抗炎的治疗方法提供了理由，以改善或预防辐射引起的脑损伤。这种竞争性更新将集中于过氧化物酶体增殖物激活的受体1和4（PPAR1，PPAR4）在改善或预防辐射引起的脑损伤（包括认知障碍）中的作用。这些PPAR是抗炎反应的有效介体。在当前的资金期间，我们已经证明了i）施用PPAR3激动剂Pioglitazone，可防止分离的WBI诱导的年轻雄性大鼠的认知障碍； ii）PPAR1 KO小鼠的辐照大脑的小胶质细胞激活增加，iii] PPAR1激动剂的给药，Fenobibrate，可防止WBI诱导的小胶质细胞激活和降低的神经发生，并且III）在PPAR1激动剂中对小胶质细胞的预处理会导致辐射1促进剂会导致辐射诱导的增长，从而增加了发炎的降低。在这种竞争性更新中，我们建议扩展我们的PPAR1研究并启动对PPAR4的研究，越来越被认为是神经保护的有前途的药理靶标。我们假设施用PPAR1和/或PPAR4激动剂不仅会改善或预防辐射引起的脑损伤，包括认知障碍，而且还会抑制脑肿瘤的生长。为了检验这一假设，我们将追求以下特定目的：1]使用分离的WBI大鼠模型，我们将确定PPAR1或PPAR4激动剂的给药是否会改善或防止辐射引起的脑损伤，包括认知障碍； 2]使用PPAR4 KO小鼠，我们将确定击倒PPAR4是否会增加辐射引起的脑损伤，而如果给药PPAR4激动剂会通过PPAR4依赖机制改善或防止辐射诱导的脑损伤； 3]使用鼠海马神经元和小胶质细胞，我们将通过抑制促炎性信号传导途径和/或上调抗炎介质的上调，确定将这些细胞与PPAR4激动剂一起孵育辐射诱导的细胞表型变化； [4]使用人神经胶质瘤细胞系和永生的正常神经胶质细胞，我们将确定用PPAR1或PPAR4激动剂治疗是否导致选择性神经胶质瘤细胞杀死。此外，我们将使用体内原位大鼠模型来确定单独或与电离辐射组合使用PPAR1或PPAR4激动剂，抑制肿瘤的生长并增加生存时间。这些目标的成功完成将成为将这些发现转化为临床试验的基础，旨在提高接受部分或WBI的癌症患者的生活质量和长期生存。公共卫生相关性：部分或WBI后，每年约有100,000名癌症患者的生存时间足够长，可以产生辐射诱发的损伤，包括认知障碍。目前尚无针对辐射引起的脑损伤的长期治疗，也没有任何有效的预防策略。 PPAR1和/或PPAR4在辐射引起的脑损伤中的介入作用应导致这些临床前发现的快速转化给诊所，从而增加了接受部分或WBI的癌症患者的治疗窗口，并影响了生活质量和长期生存。