Protection against sickle cell disease nephropathy by nitrated fatty acids

硝化脂肪酸预防镰状细胞病肾病

• 批准号: 9320025
• 负责人: Dario A Vitturi
• 金额: $ 16.08万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9320025
• 关键词: Address; Affect; African American; Age; American; Antioxidants; Attenuated; Biological Availability; Biological Models; Bone Marrow Diseases; Bone Marrow Transplantation; Cells; Chimera organism; Chronic; Chronic Kidney Failure; Complication; Development; Dietary Intervention; Dose; Drug Exposure; Drug Kinetics; Early treatment; Event; FDA approved; Fatty Acids; Fibrosis; Foundations; Functional disorder; Funding; Future; Genes; Genetic; Globin; Goals; Health; Hematological Disease; Heme; Hemoglobin; Hemolysis; Hereditary Disease; Human; Hypertension; Inflammation; Inflammatory; Injury; Ischemia; Kidney; Kidney Diseases; Knockout Mice; Knowledge; Life; Life Expectancy; Mediating; Metabolism; Mission; Modeling; Monitor; Morbidity - disease rate; Mus; Nitrates; Nitric Oxide; Oleic Acids; Oral; Organ; Orphan Drugs; Osmolar Concentration; Oxidative Stress; Oxygen; Partner in relationship; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Prevention; Prophylactic treatment; Public Health; Publishing; Quality of life; Recurrence; Regimen; Renal function; Reperfusion Injury; Reperfusion Therapy; Research; Role; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Sickle vasoocclusion; Signal Transduction; Sodium Chloride; Structure; TLR4 gene; Testing; Therapeutic Agents; Time; Toxic effect; Transgenic Mice; Transplantation; Treatment Efficacy; Tweens; United States National Institutes of Health; age related; base; design; disability; drug clearance; effective therapy; improved; inflammatory marker; injury prevention; innovation; kidney medulla; mortality; mutant; nephrogenesis; novel; oral supplementation; polymerization; prevent; prophylactic; protective effect; response; safety study; transcriptome; translational impact; vascular inflammation

Renal dysfunction is strongly associated with decreased life expectancy in sickle cell disease (SCD). Kidneys in SCD are exposed to recurrent vaso-occlusive events due to intravascular erythrocyte sickling, as well as to heme toxicity as a result of chronic hemolysis. This scenario results in renal oxidative stress, vascu- lar inflammation and decreased nitric oxide bioavailability. Current therapies only address renal complications once they are established, thus the need for safe prophylactic treatments capable of attenuating nephropathy development is critical. The long-term goal is to generate effective therapies to alleviate the development of chronic complications that result in morbidity and mortality for SCD patients. Thus, the overall objective of this application is to define the potential of nitrated fatty acids (NFA) to prevent nephropathy development in a mu- rine model of SCD. The central hypothesis is that chronic administration of the NFA nitro-oleic acid (NO2-OA) beginning at an early age will attenuate the development of renal dysfunction via Nrf2-dependent increases in antioxidant defenses and inhibiting TLR4/NFB-mediated endothelial activation and vascular inflammation. This hypothesis has been formulated based on published and unpublished research demonstrating that NFAs induce Nrf2, inhibit TLR4/NFB signaling, protect the kidney against ischemia-reperfusion injury and prevent renal fibrosis and damage in a salt-overload hypertension model. The rationale for the proposed research is that once it is established that NO2-OA attenuates SCD nephropathy, translational treatment paradigms can be developed for the protection of the kidney and other affected organs. The central hypothesis will be tested by pursuing the following specific aims: 1) Establish an equivalent NO2-OA dosing regimen for control and SCD mice; 2) Define the effects of NO2-OA in SCD renal injury; and 3) Delineate the role of Nrf2 signaling in NO2- OA protection. Since altered renal function can affect drug clearance and availability, a pharmacokinetic analy- sis will be performed to establish an equivalent dosing regimen for control and SCD mice. Correlations be- tween renal function and pharmacokinetic parameters will be utilized for real-time dosing adjustments during NO2-OA administration studies. Under the second aim, control and SCD mice will be treated with NO2-OA or oleic acid (OA) starting at 4 weeks of age for 20 weeks. Renal injury and function, as well as oxidative stress and inflammation markers will be monitored. Aim 3 will establish the contribution of Nrf2-activation to NO2-OA protection by using chimeras generated by transplanting SCD bone marrow into Nrf2-null mice. Overall, the approach is innovative because it is based on the oral supplementation of an endogenously generated NFA capable of potentiating cellular defenses and attenuating inflammation, with no toxicity at the chosen dose and that has completed phase 1 trials in humans. The proposed research is significant because it is expected to pave the way for new Nrf2/NFB/TLR4-targeting strategies to be considered for the prevention of injury to kid- neys and other organs during the course of SCD.

肾功能障碍与镰状细胞病（SCD）的预期寿命降低密切相关。 SCD中的肾脏暴露于由于血管内红细胞病的复发性血管熟悉事件，如 以及由于慢性溶血而导致的血红素毒性。这种情况导致肾脏氧化应激，Vascu- lar炎症并改善一氧化氮的生物利用度。当前疗法仅解决肾脏并发症 一旦建立了它们，就需要对能够减弱肾病的安全预防治疗 发展至关重要。长期目标是产生有效的疗法以减轻 SCD患者导致发病率和死亡率的慢性并发症。这是总体目标 应用是为了定义硝化脂肪酸（NFA）的潜力，以防止Mu-中的肾病发育 SCD的Rine模型。中心假设是长期给予NFA硝基酸（NO2-OA） 从很小的时候开始，将通过NRF2依赖性增加肾功能障碍的发展 抗氧化剂防御和抑制TLR4/NFB介导的内皮激活和血管注射。 该假设是根据已发表和未发表的研究提出的，表明NFA 诱导NRF2，抑制TLR4/NFB信号传导，保护肾脏免受缺血 - 灌注损伤并防止 盐肥大高血压模型中的肾纤维化和损伤。拟议研究的理由是 一旦确定NO2-OA减弱了SCD肾病，翻译的治疗范例就可以是 为保护肾脏和其他受影响的器官而开发。中心假设将通过 追求以下具体目的：1）建立同等的NO2-OA剂量方案进行控制和SCD 小鼠； 2）定义NO2-OA在SCD肾脏损伤中的影响； 3）描述NRF2信号在NO2-中的作用 OA保护。由于肾功能改变会影响药物的清除率和可用性，因此 将进行SIS以建立对照和SCD小鼠的等效给药方案。相关性是 - 推文肾功能和药代动力学参数将用于实时剂量调整。 NO2-OA给药研究。在第二个目标下，控制和SCD小鼠将用NO2-OA或 油酸（OA）从4周龄开始20周。肾脏损伤和功能以及氧化应激 并将监测炎症标记。 AIM 3将确定NRF2激活对NO2-OA的贡献 通过使用通过将SCD骨髓移植到NRF2-NULL小鼠中产生的嵌合体的保护。总体而言， 方法具有创新性，因为它基于内生产生的NFA的口服补充 能够增强细胞防御和衰减注射，在选定的剂量和 这已经完成了人类的第1阶段试验。拟议的研究很重要，因为它有望 为新的NRF2/NFB/TLR4靶向策略铺平道路，以预防对孩子的伤害 在SCD过程中，Neys和其他器官。