Role of inflammatory cell RAGE in collateral vessel formation

糖尿病在当今美国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。这些毁灭性的心血管并发症的一个主要原因是糖尿病患者表现出受损的侧支血管发育。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。本课题将探讨糖基化终末产物及其特异性受体在抑制侧支血管形成中的作用。我们已经开发了令人兴奋的初步数据显示，晚期糖基化终产物显着抑制侧支血管形成。而且我们 已经提出了初步的数据，证明了在这个过程中单核细胞中的信号转导的核心作用。拟议的研究将首先检查在抑制侧支血管形成的总体作用。随后的目标将研究单核细胞和T细胞中炎症细胞的具体贡献，因为我们和其他人已经证明这两种炎症细胞类型对侧支血管的形成至关重要。进一步的研究将检查活性氧作为单核细胞和T细胞中的抗肿瘤信号转导的关键信号中间体的作用。通过这些研究，我们 开发一个全面和关键的评估炎症细胞中的炎症信号传导的作用和随后对侧支血管形成的影响。

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.