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.
Experimental support for our hypotheses will provide the conceptual knowledge and systems for further translational and clinical research on a new paradigm of the mechanism of PCV. Our results may lead to the development of effective therapeutic drugs for PCV by blocking the proteolytic activity of HTRA1. Our new paradigm may also have significance for understanding other forms of retinal/choroidal vasculopathies.
|Shen, Guofu; Link, Schuyler; Kumar, Sandeep et al. (2018) Characterization of Retinal Ganglion Cell and Optic Nerve Phenotypes Caused by Sustained Intracranial Pressure Elevation in Mice. Sci Rep 8:2856|
|Mao, Renfang; Meng, Shu; Gu, Qilin et al. (2017) AIBP Limits Angiogenesis Through ?-Secretase-Mediated Upregulation of Notch Signaling. Circ Res 120:1727-1739|
|Kumar, Sandeep; Nakashizuka, Hiroyuki; Jones, Alex et al. (2017) Proteolytic Degradation and Inflammation Play Critical Roles in Polypoidal Choroidal Vasculopathy. Am J Pathol 187:2841-2857|
|Fu, Yingbin (2014) A functional approach to examine the role of HTRA1 versus ARMS2 in AMD. Invest Ophthalmol Vis Sci 55:6524|
|Kumar, Sandeep; Berriochoa, Zachary; Ambati, Balamurali K et al. (2014) Angiographic features of transgenic mice with increased expression of human serine protease HTRA1 in retinal pigment epithelium. Invest Ophthalmol Vis Sci 55:3842-50|
|Kumar, Sandeep; Berriochoa, Zachary; Jones, Alex D et al. (2014) Detecting abnormalities in choroidal vasculature in a mouse model of age-related macular degeneration by time-course indocyanine green angiography. J Vis Exp :e51061|