Mitochondria-targeting Novel Cationic Hydrazone Antioxidants for the Treatment of Preeclampsia

线粒体靶向新型阳离子腙抗氧化剂用于治疗先兆子痫

• 批准号: 10730652
• 负责人: Marianna Torok
• 金额: $ 48.59万
• 依托单位: UNIVERSITY OF MASSACHUSETTS BOSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-06 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730652
• 关键词: 3-nitrotyrosine; Abnormal placentation; Acetylcysteine; Affect; Ammonium; Angiogenesis Inhibitors; Antioxidants; Biochemical; Biological; Biological Assay; Biological Markers; Blood Pressure; Blood flow; CD44 Antigens; Cations; Cell Membrane Permeability; Cell physiology; Cells; Cellular biology; Chemicals; Complication; Data; Development; Disease; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Eclampsia; Elements; Endothelial Cells; Equilibrium; Evaluation; Exposure to; Fetal Death; Fluorine; Funding; Goals; HIF1A gene; Histologic; Homeostasis; Human; Hydrazones; Hypertension; Hypoxia; In Vitro; Institution; Invaded; Lead; Life; Liquid substance; MALDI-TOF Mass Spectrometry; Mainstreaming; Maps; Mass Spectrum Analysis; Maternal Mortality; Medical; Metabolic; Methods; Mitochondria; Mothers; Mus; NMR Spectroscopy; Nuclear Magnetic Resonance; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathway interactions; Permeability; Pharmaceutical Preparations; Plasma; Pre-Eclampsia; Pregnancy; Production; Property; Proteinuria; Publishing; Renal function; Resistance; Risk; Rodent Model; Safety; Salts; Sampling; Spiral Artery of the Endometrium; Stress; Structure; Students; Symptoms; Testing; Time; Tissues; Toxic effect; Training; Training Programs; Training and Education; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Work; antioxidant therapy; atmospheric sciences; cell injury; chemical synthesis; design; effective therapy; efficacy evaluation; extracellular; immunoreactivity; improved; in silico; in vivo; inflammatory marker; kidney dysfunction; lipophilicity; metabolic abnormality assessment; mitochondrial membrane; nitrosative stress; novel; pregnant; prevent; response; scaffold; scientific atmosphere; screening; small molecule; targeted treatment; therapeutic candidate; trophoblast; undergraduate student

SUMMARY Preeclampsia (PE) is a common, life-threatening complication in pregnancy, characterized by high blood pressure putting the mother at risk of eclampsia and kidney dysfunction. PE affects about 1–5% of pregnancies and a major cause of maternal and fetal deaths. The hallmarks of PE are the decrease in trophoblast invasion and abnormal remodeling of the spiral arteries; as well as an angiogenic/antiangiogenic imbalance. The abnormal placentation will, most likely, cause reduced feto- maternal blood flow and increased oxidative stress resulting in compromised function. There is no clear pathogenesis or cure, thus an effective treatment for PE is an unmet medical need. The primary goal of this proposal is to develop novel cationic organofluorine hydrazones for mitochondria-targeted antioxidant therapy in preeclampsia. Three key structural features will be combined to effective antioxidants: (i) a hydrazone core for improved antioxidant potential, (ii) fluorine incorporation for increased lipophilicity and membrane permeability, and (iii) introduction of quaternary ammonium salts (QASs) for the delivery of the lipophilic cation through the mitochondrial membrane. Based on our preliminary data and the results of in silico evaluations, we will design and synthesize QAS-containing organofluorine antioxidants that will be subjected to primary screening for their in vitro antioxidant activity in biochemical assays. The compounds that will show significant radical scavenging properties will be evaluated in cell-based and in vivo assays. Human primary trophoblast cells (normal or PE pregnancy) will be tested whether augmenting cell-redox function chemically by the proposed antioxidants will reduce (i) cell injury, (ii) mitochondrial stress, (iii) HIF1α production, and (iv) downstream anti-angiogenic response to hypoxia-reoxygenation. The same assays will also be carried out in human endothelial cells exposed to hypoxia-reoxygenation. In addition, time-pregnant mice will be subjected to hypoxia, to induce the main features of PE, (hypertension, proteinuria and oxidative stress), and treated with the synthetic antioxidants and the mice will be evaluated for blood pressure, renal function, histologic damage, 3-nitrotyrosine (3-NT) tissue immunoreactivity, inflammation markers and plasma biomarkers. Finally, mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy will be used to map the presence of the new cationic hydrazones in cells and tissues. These studies may lead to the development of new effective antioxidant compounds, which antagonize ROS/RNS that prevent the activation of the HIF1 pathway and therefore improve angiogenic balance and reduce the systemic effects of PE. Regarding the educational/training aspects, this work will provide a multi-environmental and interdisciplinary training to undergraduate students who will participate in each step of the project and be exposed to the research atmosphere at two different institutions.

概括 先兆子痫（PE）是妊娠期常见的危及生命的并发症，其特征是高血 压力使母亲面临子痫和肾功能障碍的风险，影响了大约 1-5% 的人。 妊娠和孕产妇和胎儿死亡的一个主要原因是PE的特点是减少。 滋养细胞侵入和螺旋动脉的异常重塑； 血管生成/抗血管生成失衡，胎盘异常很可能会导致胎儿减少。 母体血流量增加和氧化应激增加是否会导致功能受损尚不清楚。 发病机制或治愈，因此有效治疗PE是未满足的医疗需求的首要目标。 该提案旨在开发用于线粒体靶向的新型阳离子有机氟腙 先兆子痫的抗氧化疗法将结合三个关键的结构特征来有效。 抗氧化剂：(i) 腙核心可提高抗氧化潜力，(ii) 掺入氟可提高抗氧化能力 增加亲脂性和膜渗透性，以及（iii）引入季铵盐 (QAS) 用于通过线粒体膜传递亲脂性阳离子。 根据初步数据和计算机评估结果，我们将设计并合成包含 QAS 的 将对其体外抗氧化活性进行初步筛选的有机氟抗氧化剂 在生化测定中，将显示出显着的自由基清除特性的化合物是 在基于细胞和体内的检测中进行评估。 将测试所提出的抗氧化剂是否能以化学方式增强细胞氧化还原功能 减少 (i) 细胞损伤，(ii) 线粒体应激，(iii) HIF1α 产生，以及 (iv) 下游抗血管生成 对缺氧-复氧的反应也将在人内皮细胞中进行。 暴露于缺氧-复氧 此外，怀孕期间的小鼠将遭受缺氧，以至。 诱发PE的主要特征（高血压、蛋白尿和氧化应激），并用 合成抗氧化剂并对小鼠进行血压、肾功能、组织学评估 损伤、3-硝基酪氨酸 (3-NT) 组织免疫反应性、炎症标志物和血浆生物标志物。 最后，质谱（MS）和核磁共振（NMR）光谱将用于 绘制细胞和组织中新阳离子腙的存在图谱这些研究可能会导致。 开发新的有效抗氧化剂化合物，拮抗 ROS/RNS，从而防止 激活 HIF1 通路，从而改善血管生成平衡并减少全身性 在教育/培训方面，这项工作将提供一个多环境。 以及对参与项目每一步的本科生的跨学科培训 并接触两个不同机构的研究氛围。