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

基本信息

  • 批准号:
    10530637
  • 负责人:
  • 金额:
    $ 41万
  • 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
  • 起止时间:
    2019-12-15 至 2024-11-30
  • 项目状态:
    已结题

项目摘要

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.
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, 非常容易患上高血压、心血管疾病和慢性肾病, 因为未知的原因,他们长大成人。使用营养不良的怀孕小鼠模型, 产生LBW后代,发展出与LBW人类相似的病理学,拟议的研究将 研究LBW成人中血管和肾脏疾病与受 氧化应激这项研究还将研究针对血管氧化剂的新的潜在治疗策略, 调节机制来治疗高血压和肾功能不全。我们目前的研究提供了 NADPH氧化酶-4(NOX 4)驱动超氧化物介导的内皮一氧化氮增加的证据 功能障碍,巯基氧化介导的HMGB 1(可能激活TLR 4)和IL-1β的释放促进 炎症作为LBW成人经历的疾病进展的潜在驱动因素。研究 目的1将检查Nox 4缺陷小鼠和用以下药物治疗的LBW小鼠中LBW的后果, 抑制NOX 4,抑制超氧化物(包括线粒体基质中的超氧化物), NADPH氧化还原,并促进血红素生物合成,以确定其对血管功能障碍, 肾灌注和高血压发展。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,和c) 组织线粒体呼吸和功能将有助于确定驱动力的进展, 观察到的血管和肾功能障碍。使用TLR 4缺陷的小鼠和用 HMGB 1释放的抑制剂,TLR 4和IL-1β,目标2中的研究将集中于确定氧化还原 传感器HMGB 1在引起炎症、血管稀疏、肾纤维化和肾小球肥大中的作用 与高血压和肾脏疾病有关。HMGB 1-TLR 4激活的支持机制 将在从对照和LBW动物培养的细胞中定义过程。这方面的研究将审查 TLR 4在氧化型HMGB 1作用中的作用及TLR 4活化对内皮细胞的影响 线粒体功能障碍和IL-1β的释放。在目标1中提出的方法和衡量标准也将 用于记录目标2中的干预措施对氧化还原调节 疾病进展的过程和方面。假设HMGB 1中的氧化还原变化(鉴定为 通过质谱分析)可以通过所采用的治疗方法进行调节, 定义了HMGB 1的氧化还原形式,这些形式是最具病理活性的。预计这些研究 建议将记录和定义促进高血压进展的驱动因素, 心血管和慢性肾脏疾病的LBW成人,除了确定新的治疗方法, 针对驱动这种疾病进展的系统的方法。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Human Cord Blood Derived Unrestricted Somatic Stem Cells Restore Aquaporin Channel Expression, Reduce Inflammation and Inhibit the Development of Hydrocephalus After Experimentally Induced Perinatal Intraventricular Hemorrhage.
  • DOI:
    10.3389/fncel.2021.633185
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    5.3
  • 作者:
    Purohit D;Finkel DA;Malfa A;Liao Y;Ivanova L;Kleinman GM;Hu F;Shah S;Thompson C;Joseph E;Wolin MS;Cairo MS;La Gamma EF;Vinukonda G
  • 通讯作者:
    Vinukonda G
Endothelin-1 Depletion of Cartilage Oligomeric Matrix Protein Modulates Pulmonary Artery Superoxide and Iron Metabolism-associated Mitochondrial Heme Biosynthesis.
Syndecan-4 as a Marker of Endothelial Dysfunction in Patients with Resistant Hypertension.
  • DOI:
    10.3390/jcm9093051
  • 发表时间:
    2020-09-22
  • 期刊:
  • 影响因子:
    3.9
  • 作者:
    Lipphardt M;Dihazi H;Maas JH;Schäfer AK;Amlaz SI;Ratliff BB;Koziolek MJ;Wallbach M
  • 通讯作者:
    Wallbach M
Superoxide-Mediated Upregulation of MMP9 Participates in BMPR2 Destabilization and Pulmonary Hypertension Development.
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Brian Blake Ratliff其他文献

Brian Blake Ratliff的其他文献

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{{ truncateString('Brian Blake Ratliff', 18)}}的其他基金

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:
    9916890
  • 财政年份:
    2019
  • 资助金额:
    $ 41万
  • 项目类别:
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
  • 财政年份:
    2019
  • 资助金额:
    $ 41万
  • 项目类别:

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