PPARs and Radiation-induced Brain Injury

描述(由申请人提供)： 在接受部分或全脑照射(WBI)治疗后存活6个月或更长时间的原发和转移性脑肿瘤患者中，高达50%会出现进行性认知障碍；每年约有20万名患者接受这些治疗。越来越多的证据表明，氧化应激和促炎反应在放射性脑损伤中起着关键作用。这些观察结果为研究基于抗炎的治疗方法以改善或预防放射性脑损伤提供了理论基础。这一竞争性更新将集中在过氧化体增殖物激活受体1和4(PPAR1，PPAR4)在改善或预防包括认知障碍在内的放射性脑损伤中的作用。这些PPAR是抗炎反应的有效介体。在当前的资助期内，我们已经证明：i)给予PPAR3激动剂吡格列酮可预防分段性WBI导致的年轻雄性大鼠的认知障碍；ii)PPAR1 KO小鼠照射后脑内的小胶质细胞活化增加，iii)PPAR1激动剂非诺贝特可防止WBI诱导的小胶质细胞激活和神经发生减少，以及iii)用PPAR1激动剂预先处理小胶质细胞可防止辐射诱导的炎症增加。在这次竞争性更新中，我们建议扩大我们的PPAR1研究，并启动对PPAR4的研究，PPAR4越来越被认为是神经保护的一个有前途的药理靶点。我们假设，给予PPAR1和/或PPAR4激动剂不仅可以改善或预防放射性脑损伤，包括认知障碍，还可以抑制脑肿瘤的生长。为了验证这一假设，我们将追求以下具体目标：1)使用分离的WBI大鼠模型，我们将确定给予PPAR1或PPAR4激动剂是否可以改善或预防放射性脑损伤，包括认知障碍；2)使用PPAR4 KO小鼠，我们将确定i)击倒PPAR4是否会增加放射性脑损伤，以及ii)应用PPAR4激动剂是否会通过PPAR4依赖机制改善或预防放射性脑损伤；3)利用小鼠海马神经元和小胶质细胞，我们将确定这些细胞与PPAR4激动剂孵育是否通过抑制促炎信号通路和/或上调抗炎介质来调节辐射诱导的细胞表型变化；以及4)使用人胶质瘤细胞系和永生化的正常胶质细胞，我们将确定PPAR1或PPAR4激动剂处理是否导致选择性胶质瘤细胞杀伤。此外，我们将使用活体原位大鼠模型来确定单独或与电离辐射联合应用PPAR1或PPAR4激动剂是否抑制肿瘤生长和延长生存时间。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，这些试验旨在提高接受部分或WBI治疗的癌症患者的生活质量和长期存活率。公共卫生相关性：每年约有100,000名癌症患者在局部或全身照射后存活足够长的时间，以发展出包括认知障碍在内的辐射损伤。目前还没有成功的长期治疗放射性脑损伤的方法，也没有任何有效的预防策略。PPAR1和/或PPAR4在放射性脑损伤中的介入作用的确立将导致这些临床前研究结果迅速转化为临床，从而增加接受部分或WBI的癌症患者的治疗窗口，并影响他们的生活质量和长期生存。

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.