Novel approaches to attenuate lipopolysaccharide-induced inflammation

描述（申请人提供）：炎症和血管高通透性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。我们目前正在探索阻断血管炎症和增强血管稳定性的创新方法。在这方面，我们已经证明了新的蛋白Slit2抑制ccl2诱导的单核细胞趋化性。此外，我们已经证明Slit2抑制脂多糖（LPS）诱导的促进内皮细胞血管稳定性的蛋白质变化。我们的中心假设是，Slit2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是重要的。探索Slit2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）的新疗法具有重要意义。为此，我们将采用一种创新的、多学科的方法来分析Slit2的抗炎/渗透性。首先，我们将利用转基因小鼠模型系统分析Slit2对体外和体内炎症和血管通透性的影响，该模型系统在炎症刺激下表达黄色荧光蛋白（YFP），特别是LPS和趋化因子CCL2。此外，我们将绘制Slit2具有抗趋化/炎症特性并促进血管稳定性的区域。此外，我们将在ApoE-/-小鼠模型系统中确定Slit2分子在预防LPS和饮食诱导的动脉粥样硬化方面的临床应用。这些研究将为Slit2作为炎症性疾病（如动脉粥样硬化）的治疗策略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对抗动脉粥样硬化的新转化方法。

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. PUBLIC HEALTH RELEVANCE: Atherosclerosis is a leading cause of mortality from cardiovascular diseases. It is therefore important to develop novel strategies against this disease. The proposed studies will explore the Slit2-mediated novel mechanisms which regulate vascular inflammation and vascular permeability that play an important role in the development of atherosclerosis. In addition, these studies will determine the clinical utility of Slit2 in blocking diet- and LPS-induced atherosclerosis in in vivo mouse models. Ultimately, the proposed studies will provide rationale and concepts for the development of novel therapies against various inflammatory disorders, including atherosclerosis.