Role of inflammatory cell RAGE in collateral vessel formation

当今美国的糖尿病是一个爆炸性的重大公共卫生问题，直接影响心血管疾病的发病率和死亡率。这些破坏性心血管并发症的一个主要原因是糖尿病患者的侧支血管发育受损。功能性侧支血管的形成是人类对血流阻塞的主要适应机制。在这个项目中，我们将探索晚期糖基化终产物和晚期糖基化终产物特异性受体(RAGE)在抑制侧支血管形成中的作用。我们已经开发出令人兴奋的初步数据，显示晚期糖基化终末产物显著抑制侧支血管的形成。此外，我们 已经提供了初步数据，表明RAGE信号在单核细胞中在这一过程中发挥核心作用。拟议的研究将首先检查RAGE在抑制侧支血管形成方面的整体作用。随后的目标将研究RAGE在单核细胞和T细胞中的特殊作用，因为我们和其他人已经证明这两种类型的炎性细胞对侧支血管的形成至关重要。更多的研究将考察在单核细胞和T细胞中，作为RAGE信号转导的关键信号中间体的活性氧物种的作用。通过这些研究，我们将 对RAGE信号在炎症细胞中的作用以及随后对侧支血管形成的影响进行全面和关键的评估。

Diabetes in the United States today is an explosive major public health issue that directly impacts cardiovascular morbidity and mortality. One major reason for these devastating cardiovascular complications is that diabetics exhibit impaired collateral vessel development. Formation of functional collateral blood vessels is the primary adaptive mechanism in humans to blood flow obstruction. In this project we will explore the role of advanced glycation end products and the specific receptor for advanced glycation end products (RAGE) in inhibition of collateral blood vessel formation. We have developed exciting preliminary data showing that advanced glycation end products dramatically inhibit collateral vessel formation. Moreover, we have presented preliminary data that demonstrate a central role for RAGE signaling in monocytes in this process. The proposed studies will first examine the overall role of RAGE in inhibiting collateral vessel formation. Subsequent aims will study the specific contributions of RAGE in monocytes and T cells as these two inflammatory cells types have been shown by us and others to be critical for the formation of collateral blood vessels. Additional studies will examine the role of reactive oxygen species as crucial signaling intermediates in RAGE signal transduction in both monocytes and T cells. Through these studies, we will develop a comprehensive and critical assessment of the role of RAGE signaling in inflammatory cells and the subsequent impact on collateral vessel formation.