CSE regulation of vascular remodeling

CSE对血管重塑的调节

• 批准号: 10007007
• 负责人: Christopher G Kevil
• 金额: $ 42.8万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10007007
• 关键词: Address; Affect; American; Analytical Chemistry; Area; Biochemical Pathway; Biological Availability; Biology; Blood Vessels; Blood flow; Brain Hypoxia-Ischemia; Cardiovascular Diseases; Cardiovascular Physiology; Cells; Cellular biology; Chemicals; Chronic; Clinical; Cystathionine; Cysteine Desulfhydrase; Data; Disease; Endothelial Cells; Endothelium; Enzymes; Experimental Models; FDA approved; Generations; Glutathione Disulfide; Growth; Health; Hydrogen Sulfide; Hypoxia; Immune; In Vitro; Ischemia; Laboratories; Limb structure; Lyase; Macrophage Activation; Measurement; Mediator of activation protein; Metabolism; Methods; Modality; Modeling; Molecular; Molecular Target; Mus; Nitric Oxide; Organ; Participant; Pathway interactions; Peripheral; Peripheral Vascular Diseases; Peripheral arterial disease; Permeability; Play; Population; Post-Translational Protein Processing; Post-Translational Regulation; Prevalence; Prevention; Production; Proteins; Regulation; Research; Risk Factors; Role; Signal Transduction; Specimen; Sulfides; Sulfur; Testing; Therapeutic; Tissues; Treatment Efficacy; Vascular Diseases; Vascular remodeling; angiogenesis; cardiovascular health; cell growth regulation; cofactor; critical limb Ischemia; cytokine; improved; insight; macrophage; monocyte; mutant mouse model; novel; persulfides; polysulfide; recruit; response; tool

Project Summary Hydrogen sulfide synthesis and metabolism is an important participant in cardiovascular health and function. Specifically, our laboratory has shown that cystathionine g-lyase (CSE) expression and function play a critical role in ischemic vascular remodeling responses of arteriogenesis and angiogenesis. Moreover, our group has revealed important chemical biology and pathophysiological relationships between sulfide and nitric oxide metabolites in clinical vascular disease conditions, which may be important for cooperative regulation of ischemic vascular remodeling. However, numerous molecular and cellular mechanisms remain completely unknown in these responses including: the role of specific cell populations in producing discrete sulfide species during ischemic vascular remodeling, how different sulfide metabolites modulate nitric oxide (NO) bioavailability through various biochemical pathways, and mechanisms regulating rapid increases in CSE activity dependent sulfide metabolite bioavailability during hypoxia. This application will address these important unknown areas using novel tissue specific CSE mutant mouse models, cutting edge analytical chemistry measurement methods of sulfide and NO species, cellular and molecular methods to discover posttranslational regulation of CSE protein activity in response to hypoxia, and clinical tissue specimens to better understand persulfide and polysulfide during vascular remodeling and disease. Using the models and tools above, this proposal will examine the hypothesis that endothelial cell and monocyte CSE dependent polysulfide formation differentially regulates ischemic vascular remodeling and NO bioavailability. Three specific aims will be pursued to test the hypothesis including: 1) determine the mechanisms of endothelial CSE regulation of ischemic vascular remodeling and how it controls vascular cell NO bioavailability, 2) determine the mechanisms of monocyte CSE regulation of arteriogenesis, and 3) determine mechanisms of CSE activity and expression in experimental models and clinical specimens. Completion of this project will provide crucial new basic insight that is not currently available regarding mechanisms of CSE regulation and polysulfide effects on cell biology during ischemic vascular remodeling.

项目摘要 硫化氢合成和代谢是心血管健康和功能的重要参与者。 具体而言，我们的实验室表明，胱淀粉G-裂解酶（CSE）表达和功能起着关键 在动脉生成和血管生成的缺血性血管重塑反应中的作用。而且，我们的小组有 揭示了硫化物和一氧化氮之间重要的化学生物学和病理生理关系 临床血管疾病疾病中的代谢产物，这对于合作调节可能很重要 缺血性血管重塑。但是，许多分子和细胞机制都完全保持 这些反应中未知的包括：特定细胞群在产生离散硫化物物种中的作用 在缺血性血管重塑期间，不同的硫化物代谢物如何调节一氧化氮（NO） 通过各种生化途径的生物利用度以及调节CSE快速增加的机制 缺氧期间活性依赖性硫化物代谢产物生物利用度。此应用程序将解决这些 使用新型组织特异性CSE突变小鼠模型的重要未知区域，尖端分析 硫化物和无物种，细胞和分子方法的化学测量方法 响应缺氧的CSE蛋白活性的翻译后调节，以及临床组织标本 更好地了解血管重塑和疾病期间的硫化物和多硫化物。使用模型和 上面的工具，该建议将研究内皮细胞和单核细胞CSE的假设 多硫化物形成差异化调节缺血性血管重塑，而无生物利用度。三 将追求测试假设的具体目标，包括：1）确定内皮CSE的机制 脑缺血性血管重塑及其如何控制血管细胞无生物利用度的调节，2） 单核细胞CSE调节动脉生成的机制，3）确定CSE活性的机制 在实验模型和临床标本中的表达。该项目的完成将提供至关重要的 有关CSE法规和多硫化的机制，目前尚不可用的新基本见解 缺血性血管重塑期间细胞生物学的影响。