The Role of Hedgehog Interacting Protein in Sonic Hedgehog Mediated Agiogenesis

描述(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，代表了一种有前途的缺血组织修复策略。HHIP是Shh信号的细胞表面调节因子，在内皮细胞中高表达。然而，它在成人心血管生理学和Shh介导的血管生成中的作用还知之甚少。因此，我们建议确定Hedgehog相互作用蛋白在Sonic Hedgehog介导的血管生成中的作用。我们假设HHIP是Shh对血管内皮细胞影响的主要调节因子，下调HHIP将促进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，我们提出了以下特异性目标：特异性目的1：确定HHIP对内皮细胞Shh信号和反应的影响。特异性目标2：阐明Hedgehog相互作用蛋白在内皮细胞中表达的调节。特异性目标3：利用Matrigel Plug小鼠模型确定HHIP的调节是否能促进Shh介导的血管生成。在本项目结束时，我们希望确定HHIP在Shh介导的血管生成中的作用，以及HHIP的调节是否代表着朝着治疗缺血性心血管疾病的新策略迈出了有希望的一步。我们研究的长期目标是利用对病理生理学和内源性修复机制的基本见解来开发一种治疗慢性缺血性疾病的生物治疗方法。如果我们的假设是正确的，HHIP的调节可能代表着一种新的生物缺血组织修复方法。公共卫生相关性：心血管疾病是美国发病率和死亡率的头号原因，也是一个巨大的全球健康问题。修复血液供应不足的身体区域(例如：心脏、大脑、下肢)的前景看好的战略是迫切需要的。该项目将确定靶向Sonic Hedgehog途径的一个组成部分是否可以增强由该途径介导的自然愈合反应，以及这种效果的机制。

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.