Mechanisms and treatment strategies for polypoidal choroidal vasculopath

描述（由申请方提供）：息肉状脉络膜血管病变（PCV）的特征为脉络膜中存在分支血管网络，伴终末息肉状扩张。PCV也被认为是隐匿性脉络膜新生血管（CNV）的一种变体，可导致复发性浆液性渗出和视网膜下出血。我们最近报道了第一代PCV模型的转基因表达人HTRA 1，一种多功能丝氨酸蛋白酶，在小鼠视网膜色素上皮细胞（RPE）。我们发现，增加HTRA 1诱导PCV的特征，包括脉络膜血管和息肉样病变的分支网络。转基因hHTRA 1+小鼠也发生隐匿性CNV。超微结构研究显示，hHTRA 1+小鼠脉络膜血管的弹性膜和图尼卡中膜的变性，以及Bruch膜的弹性膜的降解。这些结果表明，HTRA 1介导的细胞外基质（ECM）蛋白在RPE脉络膜区域的降解是负责PCV的病理作用。该项目的目标是： 1)使用我们的hHTRA 1+小鼠模型来定义HTRA 1表达、ECM蛋白的蛋白水解和PCV进展之间的病理生理步骤; 2）使用我们从该模型获得的知识来设计新的PCV治疗策略。具体目标是：（1）检验PCV是由RPE-脉络膜区域中的ECM蛋白通过其蛋白水解活性的HTRA 1介导的降解引起的假设。(2)测试假设，在最初的 HTRA 1的“攻击”-即ECM蛋白降解-炎症过程参与PCV的进展。(3)通过抑制HTRA 1的蛋白水解活性开发治疗PCV的新策略。

DESCRIPTION (provided by applicant): Polypoidal choroidal vasculopathy (PCV) is characterized by a network of branching vessels with terminal polypoidal dilations in the choroid. PCV, which is also considered a variant of occult choroidal neovascularization (CNV), can lead to recurrent serous exudation and subretinal hemorrhage. We recently reported the generation of the first PCV model by transgenically expressing human HTRA1, a multi-functional serine protease, in mouse retinal pigment epithelium (RPE). We showed that increased HTRA1 induced characteristic features of PCV, including branching networks of choroidal vessels and polypoidal lesions. Transgenic hHTRA1+ mice also developed occult CNV. Ultrastructural study revealed degeneration of both the elastic lamina and tunica media of choroidal vessels, as well as the degradation of the elastic lamina of Bruch's membrane in hHTRA1+ mice. These results suggest that HTRA1-mediated degradation of extracellular matrix (ECM) proteins in the RPE-choroid region is responsible for its pathological role in PCV. The objectives of this project are: 1) to use our hHTRA1+ mouse model to define the pathophysilogical steps between HTRA1 expression, proteolysis of ECM proteins, and progression of PCV; 2) use our knowledge from this model to design a new PCV-treatment strategy. The Specific Aims are: (1) Test the hypothesis that PCV is caused by HTRA1 mediated degradation of ECM proteins in the RPE-choroid region through its proteolytic activity. (2) Test the hypothesis that following the initial "assault" by HTRA1- that is, ECM protein degradation - inflammatory processes are involved in the progression of PCV. (3) Develop a new strategy for treatment of PCV by inhibiting the proteolytic activity of HTRA1.