The Role of Hedgehog Interacting Protein in Sonic Hedgehog Mediated Agiogenesis

描述（由申请人提供）：Sonic Hedgehog（Shh）信号通路是组织损伤内源性反应的关键介质，代表了缺血性组织修复的一种有前景的策略。刺猬相互作用蛋白（Hhip）是Shh信号传导的细胞表面调节剂，其已被证明在内皮细胞上高度表达。然而，其在成人心血管生理学和Shh介导的血管生成中的作用知之甚少。因此，我们建议确定刺猬相互作用蛋白在刺猬介导的血管生成中的作用。我们假设Hhip是Shh对内皮细胞作用的主要调节因子，Hhip的下调将增强Shh介导的血管生成。为了研究Hhip在Shh介导的血管生成中的作用，我们提出了以下具体目标：具体目标#1：确定Hhip对内皮细胞中Shh信号传导和响应的影响具体目标#2：阐明内皮细胞中刺猬相互作用蛋白表达的调节具体目标#3：使用基质胶塞小鼠模型确定Hhip的调节是否可以增强Shh介导的血管生成。在这个项目的结论，我们希望已经确定的作用，HHIP在Shh介导的血管生成和HHIP的调制是否代表了一个有前途的一步，缺血性心血管疾病的新的治疗策略。我们研究的长期目标是利用关于病理生理学和内源性修复机制的基本见解来开发慢性缺血性疾病的生物治疗。如果我们的假设是正确的，那么Hip的调节可能代表生物缺血组织修复的新方法。公共卫生相关性：在美国，心血管疾病是发病率和死亡率的头号原因，并且是一个巨大的全球健康问题。迫切需要有希望的策略来修复身体（例如：心脏，大脑，下肢）供血不足的区域。该项目将确定靶向Sonic Hedgehog通路的一个组成部分是否可以增强由该通路介导的自然愈合反应以及这种效应的机制。

DESCRIPTION (provided by applicant): The Sonic Hedgehog (Shh) signaling pathway is a key mediator of the endogenous response to tissue injury and represents a promising strategy for ischemic tissue repair. Hedgehog Interacting Protein (Hhip) is a cell surface regulator of Shh signaling which has been shown to be highly expressed on endothelial cells. However, its role in adult cardiovascular physiology and in Shh mediated angiogenesis is poorly understood. Therefore, we propose to determine the role of Hedgehog Interacting Protein in Sonic Hedgehog mediated angiogenesis. We hypothesize that Hhip is a major regulator of the effects of Shh on the endothelium and that downregulation of Hhip will enhance Shh mediated angiogenesis. To investigate the role of Hhip in Shh mediated angiogenesis, we propose the following specific aims: Specific Aim #1: Determine the effect of Hhip on Shh signaling and response in endothelial cells Specific Aim #2: Elucidate the regulation of Hedgehog Interacting Protein expression in endothelial cells Specific Aim #3: Determine whether modulation of Hhip can enhance Shh mediated angiogenesis using the Matrigel plug mouse model. At the conclusion of this project, we expect to have determined the role of Hhip in Shh mediated angiogenesis and whether modulation of Hhip represents a promising step forward toward a new treatment strategy for ischemic cardiovascular diseases. The long-term goal of our investigations is to leverage basic insights about pathophysiology and endogenous repair mechanisms to develop a biological treatment for chronic ischemic diseases. If our hypothesis is correct, modulation of Hhip could represent a novel approach for biological ischemic tissue repair. Public Health Relevance: cardiovascular diseases are the number one cause of morbidity and mortality in the United States and are an immense global health issue. Promising strategies to repair areas of the body (for example: heart, brain, lower limbs) that suffer from inadequate blood supply are desperately needed. This project will determine whether targeting a component of the Sonic Hedgehog pathway can enhance the natural healing response mediated by this pathway and the mechanisms for this effect.