CSE regulation of vascular remodeling

CSE对血管重塑的调节

基本信息

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
项目类别：
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

项目摘要

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.

项目概要硫化氢的合成和代谢是心血管健康和功能的重要参与者。具体来说，我们的实验室已表明胱硫醚 G-裂解酶 (CSE) 的表达和功能在在动脉生成和血管生成的缺血性血管重塑反应中的作用。另外，我们组还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学关系临床血管疾病条件下的代谢物，这对于协同调节可能很重要缺血性血管重塑。然而，许多分子和细胞机制仍然完全保留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过程中，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的硫化物代谢物生物利用度。该应用程序将解决这些问题使用新型组织特异性 CSE 突变小鼠模型、尖端分析的重要未知领域硫化物和NO物种的化学测量方法，发现的细胞和分子方法 CSE 蛋白活性响应缺氧的翻译后调节，以及临床组织标本更好地了解血管重塑和疾病过程中的过硫化物和多硫化物。使用模型和工具上述，该提案将检验内皮细胞和单核细胞 CSE 依赖的假设多硫化物的形成对缺血性血管重塑和一氧化氮生物利用度有不同的调节作用。三检验假设的具体目标包括：1）确定内皮 CSE 的机制缺血性血管重塑的调节及其如何控制血管细胞 NO 生物利用度，2) 确定单核细胞 CSE 调节动脉生成的机制，3) 确定 CSE 活性的机制以及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目前尚无关于 CSE 监管和多硫化物机制的新基本见解缺血性血管重塑过程中对细胞生物学的影响。