Novel approaches to attenuate lipopolysaccharide-induced inflammation

减轻脂多糖诱导的炎症的新方法

• 批准号: 8291967
• 负责人: Ramesh K. Ganju
• 金额: $ 19.06万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8291967
• 关键词: Adherens Junction; Adhesions; Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Attenuated; Biological Models; Blood Vessels; CCL2 gene; Cardiovascular Diseases; Cell Adhesion; Cells; Chemotaxis; Clinical; Crescentic Glomerulonephritis; Data; Development; Diet; Disease; Disease Progression; Endothelial Cells; Endothelium; Functional disorder; Goals; Growth; Imaging technology; Immune; In Vitro; Inflammation; Inflammatory; Ischemia; Lead; Leukocyte Chemotaxis; Leukocytes; Link; Lipopolysaccharides; Maps; Mediating; Membrane; Molecular; Neuroglia; Neurons; Pathway interactions; Permeability; Play; Process; Property; Proteins; Role; Sclerosis; Sepsis; Signal Pathway; Stimulus; T-Lymphocyte; Therapeutic; Tight Junctions; Transgenic Mice; Tweens; Vascular Permeabilities; Work; base; beta catenin; cadherin 5; chemokine; combat; in vivo; innovation; insight; migration; monocyte; mortality; mouse model; new therapeutic target; novel; novel strategies; prevent; response; secretory protein; trafficking; translational approach; tumor; vascular inflammation

DESCRIPTION (provided by applicant): Inflammation and vascular hyperpermeability have been shown to play an important role in the development of cardiovascular diseases, especially atherosclerosis. We are currently exploring innovative approaches to block vascular inflammation and enhance vascular stability. In this regard, we have shown that the novel protein Slit2 inhibits CCL2-induced chemotaxis of monocytes. Furthermore, we have shown that Slit2 inhibits lipopolysaccharides (LPS)-induced changes in proteins that promote vascular stability in endothelial cells. Our central hypothesis is that Slit2 will have a broad-based effect in inhibiting monocyte chemotaxis/transendothelial migration, leukocyte endothelial interaction and vascular permeability. These processes are important during the development of atherosclerosis. Exploring how Slit2 affects vascular dysfunction is of fundamental importance for developing novel therapies against various inflammatory disorders, including atherosclerosis. To this end, we will use an innovative, multi-disciplinary approach to analyze the anti-inflammatory/permeability properties of Slit2. First, we will analyze the effect of Slit2 on inflammation and vascular permeability in vitro and in vivo using a transgenic mouse model system expressing yellow fluorescent protein (YFP) in response to inflammatory stimuli, especially LPS and chemokine CCL2. Furthermore, we will map the region of Slit2 that possesses the anti-chemotactic/inflammatory properties and promotes vascular stability. Additionally, we will determine the clinical utility of the Slit2 molecule to prevent LPS and diet-induced atherosclerosis in ApoE-/- mouse model systems. These studies will provide novel rationales and concepts for the development of Slit2 as a therapeutic strategy for inflammatory disorders, such as atherosclerosis. Ultimately, insight gained from our proposed studies may help us to explore new translational approaches to combat atherosclerosis.

描述（由申请人提供）：炎症和血管通透性过高已被证明在心血管疾病，特别是动脉粥样硬化的发展中起重要作用。我们目前正在探索创新的方法来阻断血管炎症和增强血管稳定性。在这方面，我们已经表明，新的蛋白质Slit 2抑制CCL 2诱导的单核细胞的趋化性。此外，我们已经表明，Slit 2抑制脂多糖（LPS）诱导的蛋白质的变化，促进血管内皮细胞的稳定性。我们的中心假设是Slit 2在抑制单核细胞趋化性/跨内皮迁移、白细胞内皮相互作用和血管通透性方面具有广泛的作用。这些过程在动脉粥样硬化的发展过程中很重要。探索Slit 2如何影响血管功能障碍对于开发针对各种炎症性疾病（包括动脉粥样硬化）的新疗法至关重要。为此，我们将使用创新的多学科方法来分析Slit 2的抗炎/渗透性特性。首先，我们将分析Slit 2在体外和体内对炎症和血管通透性的影响，使用表达黄色荧光蛋白（YFP）的转基因小鼠模型系统来响应炎症刺激，特别是LPS和趋化因子CCL 2。此外，我们将绘制具有抗趋化/炎症特性并促进血管稳定性的Slit 2区域。此外，我们将确定Slit 2分子在ApoE-/-小鼠模型系统中预防LPS和饮食诱导的动脉粥样硬化的临床效用。这些研究将为Slit 2作为炎症性疾病（如动脉粥样硬化）的治疗策略的发展提供新的理论基础和概念。最终，从我们提出的研究中获得的见解可能有助于我们探索新的转化方法来对抗动脉粥样硬化。