PPARs and Radiation-induced Brain Injury

PPAR 和辐射引起的脑损伤

• 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
• 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

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）： 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性和转移性脑肿瘤患者中，高达50%发生进行性认知障碍;每年约有200，000例患者接受这些治疗。越来越多的证据表明，氧化应激和促炎反应在辐射诱导的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辐射诱导的脑损伤提供了理论基础。这种竞争性更新将集中在过氧化物酶体增殖物激活受体1和4（PPAR 1，PPAR 4）在改善或预防辐射诱导的脑损伤，包括认知障碍的作用。这些PPARs是抗炎反应的有效介质。在当前的资助期内，我们已经证明i）给予PPAR 3激动剂吡格列酮可预防年轻成年雄性大鼠中分次WBI诱导的认知障碍; ii）PPAR 1 KO小鼠的经辐照的脑具有增加的小胶质细胞活化，iii）施用PPAR 1激动剂非诺贝特防止WBI诱导的小胶质细胞活化和减少的神经发生，和iii）用PPAR 1激动剂预处理小胶质细胞防止辐射诱导的炎症增加。在这次竞争性更新中，我们建议扩展我们的PPAR 1研究，并启动对PPAR 4的研究，PPAR 4越来越被认为是一个有前途的神经保护药理学靶点。我们假设给予PPAR 1和/或PPAR 4激动剂不仅可以改善或预防辐射诱导的脑损伤，包括认知障碍，而且还可以抑制脑肿瘤的生长。为了检验这一假设，我们将追求以下具体目的：1]使用分次WBI大鼠模型，我们将确定施用PPAR 1或PPAR 4激动剂是否将改善或预防辐射诱导的脑损伤，包括认知损害; 2]使用PPAR 4 KO小鼠，我们将确定i]敲低PPAR 4是否会增加辐射诱导的脑损伤，和ii]如果施用PPAR 4激动剂将通过PPAR 4依赖性机制改善或预防辐射诱导的脑损伤; 3]使用鼠海马神经元和小胶质细胞，我们将确定这些细胞与PPAR 4激动剂一起孵育是否通过抑制细胞表型中的前-炎症信号传导途径和/或抗炎介质的上调;和4]使用人神经胶质瘤细胞系和永生化的正常神经胶质细胞，我们将确定用PPAR 1或PPAR 4激动剂处理是否导致选择性神经胶质瘤细胞杀伤。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施用PPAR 1或PPAR 4激动剂是否抑制肿瘤生长并增加存活时间。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，这些临床试验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率。公共卫生关系：每年约有100，000名癌症患者在部分或全脑损伤后存活足够长的时间，从而出现辐射诱导的损伤，包括认知障碍。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。PPAR 1和/或PPAR 4在辐射诱导的脑损伤中的干预作用的建立应导致这些临床前发现快速转化为临床，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。