Inhibition of fatty acid amide hydrolase as a novel strategy to prevent nephrotoxicity of cisplatin.

抑制脂肪酸酰胺水解酶作为预防顺铂肾毒性的新策略。

• 批准号: 10513011
• 负责人: Ningjun Li
• 金额: $ 22.37万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10513011
• 关键词: 2-arachidonylglycerol; Address; Agonist; Anabolism; Applications Grants; Arachidonic Acids; Attenuated; Binding; Breast; CNR1 gene; Cannabidiol; Cells; Cisplatin; Clinical; Coxibs; Data; Diglycerides; Dose-Limiting; Endocannabinoids; Enzymes; Ethanolamines; FAAH inhibitor; Fatty Acids; Genetic; Head and neck structure; Hydrolysis; Injury to Kidney; Intervention; Investigation; Kidney; Kidney Diseases; Knockout Mice; Ligands; Lung; Malignant Neoplasms; Metabolic; Monoacylglycerol Lipases; Mus; Neuraxis; Organ; Ovarian; PTGS2 gene; Patients; Peripheral; Pharmacology; Play; Prevention strategy; Production; Reporting; Role; Route; Serine Hydrolase; Signal Pathway; Solid; Supplementation; Testing; Therapeutic; Toxic effect; Tubular formation; anandamide; antagonist; anticancer treatment; autocrine; base; cannabinoid receptor; endogenous cannabinoid system; fatty acid amide hydrolase; kidney dysfunction; lipoprotein lipase; nephrotoxicity; novel; novel strategies; novel therapeutic intervention; novel therapeutics; paracrine; prevent; receptor; renal damage; systemic intervention; targeted delivery; therapeutic target; tissue injury

Nephrotoxicity is a primary dose-limiting toxicity for cisplatin, a potent first-line therapy for many solid malignancies. The mechanistic basis for cisplatin-induced kidney damage is not fully understood and no efficient management strategies are currently available. The endocannabinoid (EC) system, which has been initially focused on the central nervous system, also plays important roles in the peripheral organs, including the kidneys. The most well-characterized ECs are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The biosynthesis of AEA is through the hydrolysis of N-arachidonoyl-phosphatidyl-ethanolamines via at least three distinct biosynthetic routes. The 2-AG is produced by diacylglycerol lipases, which hydrolyze 2-arachidonoyl-containing diacylglycerols (DAG) to generate 2-AG. After production, ECs bind to the local cannabinoid receptors (CB1 and CB2) in an autocrine or paracrine manner. It has been shown that EC system participates in different kidney diseases, including cisplatin-induced nephrotoxicity (CIN), and that interventions of CB receptors are promising therapeutic strategies. Surprisingly, majority of studies focus on CB receptors, and little is known about roles of ECs metabolic enzymes in kidney damages. It is important to address this significant gap and imperative to investigate the role of ECs enzymes in kidney diseases. A recent study showed that in cisplatin-treated mice, AEA was significantly increased while 2-AG had no change in the kidneys and that inhibition of CB1 receptors attenuated the cisplatin-induced renal dysfunction, suggesting that endocannabinoid system through CB1 receptors promotes cisplatin-induced kidney injury. We initially intended to test whether FAAH inhibition, which results in increased levels of AEA, would aggravate the CIN. Surprisingly, CIN was dramatically attenuated in FAAH KO mice, suggesting that the increased levels of AEA is actually protective in CIN. The elevation of AEA levels after FAAH inhibition could also result in reduced levels of AEA-FAAH-derived arachidonic acid (AA) and increased levels of AEA-COX2-derived prostamides. Our preliminary data demonstrated that the protection by FAAH inhibitor was reversed by the substrate-selective COX2 inhibitor LM4131 (inhibits AEA-COX2, not AA- COX2), but not by the supplementation of AA, nor the blocking CB receptors. Based on the above information, the hypothesis to be tested is that FAAH inhibition protects the kidneys against CIN via AEA-COX2-derived prostamides. The following Aims are proposed to test the hypotheses. Aim 1: To determine whether inhibition of FAAH protects the kidneys against CIN. Studies will use genetic and pharmacological as well as both systemic and kidney-targeted approaches for FAAH inhibition. Aim 2: to determine whether AEA-COX2-derived prostamides are the downstream signaling pathway responsible for the renoprotection after FAAH inhibition in CIN. Aim 3: To establish that inhibition of FAAH will not interfere with the antitumor actions of cisplatin. The findings from these proposed studies will suggest that inhibition of FAAH is new therapeutic strategy for the prevention and treatment of CIN.

肾毒性是顺铂的主要剂量限制性毒性，这是许多固体的有效的一线治疗 恶性肿瘤。顺铂引起的肾脏损伤的机械基础尚不完全了解，没有有效的效率 管理策略当前可用。内源性大麻素（EC）系统，最初是 专注于中枢神经系统，在包括肾脏在内的外围器官中也起着重要作用。 最良好的EC是Anandamide（AEA）和2-芳基烯丙基甘油（2-AG）。生物合成 AEA的通过N-芳基多烯酰基磷脂酰乙醇胺的水解通过至少三个不同的 生物合成路线。 2-AG由二酰基甘油脂肪酶产生，该脂肪酶水解2-芳烃 二酰基甘油（DAG）产生2-AG。生产后，EC与局部大麻素受体结合（CB1和 CB2）以自分泌或旁分泌方式。已经显示EC系统参与不同的肾脏 疾病，包括顺铂诱导的肾毒性（CIN），CB受体的干预措施有望 治疗策略。令人惊讶的是，大多数研究都集中在CB受体上，对 肾脏损害中的ECS代谢酶。解决这一巨大差距很重要，必须 研究ECS酶在肾脏疾病中的作用。最近的一项研究表明，在顺铂治疗的小鼠中， AEA显着增加，而2Ag肾脏没有变化，并且抑制CB1受体 减弱了顺铂诱导的肾功能障碍，表明内源性大麻素系统通过CB1 受体促进顺铂诱导的肾损伤。我们最初打算测试FAAH是否抑制 导致AEA水平升高，会加剧CIN。令人惊讶的是，Cin急剧衰减 法族KO小鼠，表明AEA水平的增加实际上是CIN中的保护性。 AEA的海拔 FAAH抑制后的水平也可能导致AEA-FAAH衍生的花生四烯酸（AA）和 AEA-COX2衍生的前列酰胺的水平增加。我们的初步数据表明，通过 FAAH抑制剂被底物选择性COX2抑制剂LM4131逆转（抑制AEA-COX2，而不是AA- COX2），但不是通过补充AA，也不是通过阻断CB受体的。基于上述信息， 要检验的假设是FAAH抑制作用通过AEA-Cox2衍生 前列腺酰胺。提出了以下目的来检验假设。目标1：确定是否抑制 法族人保护肾脏免受CIN的侵害。研究将使用遗传学和药理以及两种全身性 以及针对肾脏的法族抑制方法。目标2：确定AEA-Cox2衍生的 前列腺酰胺是FAAH抑制后负责肾脏保护的下游信号传导途径 CIN。目的3：确定对法族的抑制不会干扰顺铂的抗肿瘤作用。这 这些提出的研究的结果将表明，抑制法族是新的治疗策略 CIN的预防和处理。