Novel vascular guidance mechanisms

描述（由申请人提供）：稳定性和再生之间的平衡对维持血管系统功能至关重要。在成熟的循环系统中，内皮通过控制血管内腔室和血管外腔室之间的液体、营养物质和细胞运输，提供关键的屏障和调节功能。血管损伤引起炎症反应，刺激细胞因子和生长因子的释放。这些因素削弱内皮细胞-细胞连接，刺激迁移和增殖，并为重塑和再生铺平道路。因此，在血管内皮中，维持血管稳态/稳定的信号和刺激再生/不稳定的信号之间存在着不断的拉锯战。这种竞争性更新的核心假设是，Slit-Robo4是一种内源性配体受体途径，驱动平衡走向稳态/稳定。如果这个模型是正确的，那么Robo4信号可能会对抗多种血管生成和炎症细胞因子介导的损伤、缺血和炎症的不稳定影响。具体目的1：阐明Robo4信号转导的机制。特异性目的2：确定Slit-Robo4是否是钝化血管对细胞因子反应的广泛平台。在我们的研究结束时，我们希望我们的贡献将是证明Robo4是一个广泛的血管稳定程序，并确定其下游信号级联。公共卫生相关性：在我们的研究结束时，我们希望我们的贡献将是证明Robo4是一个广泛的血管稳定程序，并确定其下游信号级联。在追求这些目标的过程中，我们希望证明激活这种血管稳定程序将减少各种缺血性和炎症性疾病的病理性内皮细胞高通透性。

DESCRIPTION (provided by applicant): The equilibrium between stability and regeneration is critical to maintaining a functional vasculature. In the mature circulatory system, the endothelium provides critical barrier and regulatory functions by controlling fluid, nutrient and cellular transport between intravascular and extravascular compartments. Vascular injury induces an inflammatory response that stimulates the release of cytokines and growth factors. These factors weaken endothelial cell-cell junctions, stimulate migration and proliferation, and pave the way for remodeling and regeneration. Thus, there is constant tug-of-war within the vascular endothelium between signals that maintain vascular homeostasis/stability and signals that incite regeneration/instability. The central hypothesis for this competitive renewal is that Slit-Robo4 is an endogenous ligand receptor pathway that drives the balance toward homeostasis/stability. If this model is correct, then Robo4 signal might oppose the destabilizing influences of injury, ischemia, and inflammation mediated by a variety of angiogenic and inflammatory cytokines. Specific Aim 1: Elucidate the mechanism of Robo4 signaling. Specific Aim 2: Determine whether Slit-Robo4 is a broad platform for blunting the vascular response to cytokines. At the conclusion of our studies, we hope our contribution will be to demonstrate that Robo4 is a broad vascular stabilization program and to define its downstream signaling cascade. PUBLIC HEALTH RELEVANCE: At the conclusion of our studies, we hope our contribution will be to demonstrate that Robo4 is a broad vascular stabilization program and to define its downstream signaling cascade. In pursuing these objectives we hope to demonstrate that activating this vascular stability program will reduce pathologic endothelial hyperpermeability in a variety of ischemic and inflammatory diseases.