课题基金 / 基金详情

NOX4-associated oxidative stress mediates vascular and kidney impairment in the low birth weight adult

NOX4-associated oxidative stress mediates vascular and kidney impairment in the low birth weight adult
NOX4相关的氧化应激介导低出生体重成人的血管和肾脏损伤
批准号:
10320920
负责人:
Brian Blake Ratliff
金额:
$41.0万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-12-15 至 2023-11-30

项目摘要

项目成果

Brian Blake Ratliff的其他基金

相似基金

相关文献

中文摘要
翻译
项目摘要 新生儿医学的最新进展增加了低出生体重 (LBW) 婴儿的数量。 极易患高血压、心血管疾病和慢性肾病 随着成年期的成熟,未知的原因。使用营养不良的怀孕小鼠模型 产生与 LBW 人类相似的病理学的 LBW 后代,拟议的研究将 研究 LBW 成人的血管和肾脏疾病与受调节系统的关系 氧化应激。该研究还将探讨针对血管氧化剂的新的潜在治疗策略 治疗高血压和肾功能障碍的调节机制。我们目前的研究提供了 NADPH 氧化酶 4 (NOX4) 驱动超氧化物介导的内皮一氧化氮增加的证据 功能障碍,硫醇氧化介导的 HMGB1(可能激活 TLR4)和 IL-1β 的释放得到促进 炎症是 LBW 成人疾病进展的潜在驱动因素。研究于 目标 1 将检查 LBW 对 Nox4 缺陷小鼠和接受以下药物治疗的 LBW 小鼠的影响: 抑制NOX4,清除超氧化物(包括线粒体基质中的超氧化物),稳定细胞质 NADPH 氧化还原,并促进血红素生物合成,以确定它们对血管功能障碍、血管损伤的影响 肾灌注和高血压的发生。 a) 氧化还原和代谢指标的测量或 与这些方法相关的信号传导机制,b)血管功能的改变,以及c) 组织线粒体呼吸和功能将有助于确定疾病进展的驱动力 观察到的血管和肾功能障碍。使用缺乏 TLR4 的小鼠和接受过 TLR4 治疗的动物 HMGB1 释放、TLR4 和 IL-1β 抑制剂,目标 2 中的研究将侧重于确定氧化还原的作用 传感器 HMGB1 导致炎症、血管稀疏、肾纤维化和肾小球肥大 与高血压和肾脏疾病有关。 HMGB1-TLR4激活的支持机制 过程将在从对照和低体重动物培养的细胞中定义。针对这一目标的研究将考察 TLR4 在 HMGB1 氧化形式的作用中的作用,以及 TLR4 激活对内皮细胞的影响 线粒体功能障碍和 IL-1β 释放。目标 1 中采取的方法和测量也将 用于记录目标 2 中的干预措施对氧化还原监管之间关系的影响 疾病进展的过程和方面。据推测,HMGB1 中的氧化还原变化(已确定 通过质谱分析)可以通过所采用的疗法进行调节,从而有助于 定义病理学上最活跃的 HMGB1 氧化还原形式。预计研究 提议将记录和定义促进高血压进展的驱动因素, 除了确定新的治疗方法外,低出生体重成人的心血管和慢性肾脏疾病 针对驱动此类疾病进展的系统的方法。
英文摘要
PROJECT ABSTRACT Recent advances in neonatal medicine have increased the population of low birth weight (LBW) babies that are incredibly susceptible for development of hypertension, cardiovascular disease and chronic kidney disease for unknown reasons as they mature through adulthood. Using an undernourished pregnant mouse model to generate LBW offspring that develop pathologies similar to those in LBW humans, the proposed studies will investigate the association of vascular and kidney disease in the LBW adult with systems regulated by oxidative stress. The study will also examine new potential therapeutic strategies that target vascular oxidant- regulated mechanisms to treat hypertension and renal dysfunction. Our current studies have provided evidence for NADPH oxidase-4 (NOX4) driven increases in superoxide-mediated endothelial nitric oxide dysfunction, thiol oxidation-mediated release of HMGB1 (which potentially activates TLR4) and IL-1β promoted inflammation as potential driving factors in the disease progression that the LBW adult experiences. Studies in Aim 1 will examine the consequences of LBW in Nox4 deficient mice and in LBW mice treated with agents that inhibit NOX4, scavenge superoxide (including superoxide in the mitochondrial matrix), stabilize cytosolic NADPH redox, and promote heme biosynthesis to define their impact on vascular dysfunction, impairment of renal perfusion and hypertension development. Measurements of a) redox and metabolic indicators or signaling mechanisms related to these approaches, b) alterations in vascular function, and c) alterations in tissue mitochondrial respiration and function will be made to help define driving forces in the progression of vascular and renal dysfunction that is observed. Using mice deficient in TLR4, and animals treated with inhibitors of HMGB1 release, TLR4 and IL-1β, studies in Aim 2 will focus on defining the role that the redox sensor HMGB1 has in causing inflammation, vascular rarefaction, renal fibrosis and glomerular hypertrophy associated with hypertension and kidney disease. Supporting mechanisms for the HMGB1-TLR4 activation processes will be defined in cells cultured from control and LBW animals. Studies in this aim will examine the role of TLR4 in the actions of oxidized forms of HMGB1, and the impact of TLR4 activation on endothelial cell mitochondrial dysfunction and release of IL-1β. The approaches and measurements made in Aim 1 will also be used to document the impact of the interventions in Aim 2 on relationships between redox regulatory processes and aspects of disease progression. It is hypothesized that the redox changes in HMGB1 (identified by mass spectral analyses) can potentially be modulated by the therapies employed in ways that could help define the HMGB1 redox forms that are the most pathologically active. It is anticipated that the studies proposed will document and define the driving factors that promote the progression of hypertension, cardiovascular and chronic kidney disease in LBW adults, in addition to identifying novel therapeutic approaches that target the systems that drive such disease progression.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
NOX4-associated oxidative stress mediates vascular and kidney impairment in the low birth weight adult
  • 批准号:
    9916890
  • 项目类别:
  • 资助金额:
    $41.0万
  • 财政年份:
    2019
  • 负责人:
    Brian Blake Ratliff
  • 依托单位:
NOX4-associated oxidative stress mediates vascular and kidney impairment in the low birth weight adult
  • 批准号:
    10530637
  • 项目类别:
  • 资助金额:
    $41.0万
  • 财政年份:
    2019
  • 负责人:
    Brian Blake Ratliff
  • 依托单位:
海外基金