Mechanisms and treatment strategies for polypoidal choroidal vasculopath

描述(申请人提供)：息肉状脉络膜血管病(PCV)的特征是脉络膜中有分支血管网络并伴有终末息肉样扩张。PCV也被认为是隐匿性脉络膜新生血管(CNV)的变种，可导致复发性浆液性渗出和视网膜下出血。我们最近报道了在小鼠视网膜色素上皮(RPE)中转基因表达人HTRA1(一种多功能丝氨酸蛋白酶)，从而建立了第一个PCV模型。我们发现，HTRA1的增加导致了PCV的特征，包括脉络膜血管的分支网络和息肉样病变。转hHTRA1+基因的小鼠也出现了隐匿性CNV。超微结构观察发现，hHTRA1+小鼠脉络膜血管弹力层和中膜均变性，Bruchs膜弹力层变性。这些结果表明，HTRA1介导的细胞外基质(ECM)蛋白在RPE脉络膜区域的降解是其在PCV中的病理作用。该项目的目标是： 1)使用我们的hHTRA1+小鼠模型来确定HTRA1表达、ECM蛋白降解和PCV进展之间的病理生理步骤；2)利用我们从这个模型中获得的知识来设计新的PCV治疗策略。其具体目的是：(1)验证PCV是由HTRA1介导的RPE脉络膜区ECM蛋白通过其蛋白分解活性降解而引起的假说。(2)检验假设：遵循首字母 HTRA1的“攻击”--也就是ECM蛋白降解--炎症过程参与了PCV的进展。(3)通过抑制HTRA1的蛋白分解活性，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.