Novel vascular guidance mechanisms

描述（由申请人提供）：稳定性和再生之间的平衡对于维持功能性血管系统至关重要。在成熟的循环系统中，内皮通过控制血管内和血管外隔室之间的流体、营养物和细胞运输提供关键的屏障和调节功能。血管损伤诱导炎症反应，刺激细胞因子和生长因子的释放。这些因子削弱内皮细胞-细胞连接，刺激迁移和增殖，并为重塑和再生铺平道路。因此，在维持血管稳态/稳定性的信号和刺激再生/不稳定性的信号之间，在血管内皮内存在持续的拔河。这种竞争性更新的中心假设是，Slit-Robo 4是一种内源性配体受体途径，它驱动平衡向稳态/稳定性发展。如果这个模型是正确的，那么Robo 4信号可能会对抗由各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。具体目标1：阐明Robo 4信号转导机制。具体目标2：确定Slit-Robo 4是否是一个广泛的平台，用于减弱血管对细胞因子的反应。在我们的研究结束时，我们希望我们的贡献将是证明Robo 4是一个广泛的血管稳定程序，并定义其下游信号级联。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Robo 4是一个广泛的血管稳定程序，并定义其下游信号级联。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性程序将减少各种缺血性和炎症性疾病中的病理性内皮通透性过高。

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.