Retinal neovascularization and choroidal neovascularization (CNV), as occur in retinopathy of prematurity (ROP) and age-related macular degeneration (AMD), are major causes of blindness. A significant role for the proangiogenic vascular endothelial growth factor (VEGF) has been established in these diseases. Therefore, intravitreal administration of anti-VEGF has been greatly pursued as treatment for exudative AMD and ROP. However, intravitreal administration of anti-VEGF enters the general circulation resulting in prolonged inhibition of VEGF, which may cause off-target effects including renal thrombotic microangiopathy, myocardial infarction and stroke. Bcl-2 is a key mediator of downstream events in response to both pro- and anti-angiogenic factors, including VEGF and thrombospondin-1 (TSP1). Bcl-2 has been a target of cancer therapeutic regimens due to its ability to selectively disrupt tumor blood vessels and induce apoptosis. Our hypothesis is that inhibition of bcl-2 expression and/or activity will prevent choroidal and retina neovascularization. This hypothesis is supported by our studies showing that VEGF-driven retinal neovascularization requires bcl-2 expression. In addition, removal of a single allele of bc-2 is sufficient to attenuate CNV. In this proposal we take the innovative approach of using bcl-2 antagonists in concert with histone deacetylase (HDAC) inhibitors to selectively prevent ocular neovascularization. Identification of whether bcl-2 expression is essential in endothelial cells and/or perivascular supporting cells for choroidal and retinal neovascularization will give us further insight as to whether both types of neovascularization rely on similar pathways. These studies in combination will give us a unique perspective to identify the most effective treatment strategies to inhibit retinal and choroidal neovascularization and avoid off-target systemic effects.
Bcl-2 plays essential roles during angiogenesis, development and in the pathogenesis of many diseases. Our hypothesis is that inhibition of Bcl-2 expression and/or activity prevents choroidal and retinal neovascularization. Understanding the role Bcl-2 plays in choroidal and retinal neovascularization is critical for the development of new treatment modalities for the prevention of ocular diseases with a neovascular component.
| Dharmarajan, Subramanian; Fisk, Debra L; Sorenson, Christine M et al. (2017) Microglia activation is essential for BMP7-mediated retinal reactive gliosis. J Neuroinflammation 14:76 |
| Liu, Wenzhong; Wang, Shoujian; Soetikno, Brian et al. (2017) Increased Retinal Oxygen Metabolism Precedes Microvascular Alterations in Type 1 Diabetic Mice. Invest Ophthalmol Vis Sci 58:981-989 |
| Zaitoun, Ismail S; Johnson, Ryan P; Jamali, Nasim et al. (2015) Endothelium Expression of Bcl-2 Is Essential for Normal and Pathological Ocular Vascularization. PLoS One 10:e0139994 |
| Fei, Ping; Palenski, Tammy L; Wang, Shoujian et al. (2015) Thrombospondin-2 Expression During Retinal Vascular Development and Neovascularization. J Ocul Pharmacol Ther 31:429-44 |
| Park, Sunyoung; Sorenson, Christine M; Sheibani, Nader (2015) PECAM-1 isoforms, eNOS and endoglin axis in regulation of angiogenesis. Clin Sci (Lond) 129:217-34 |
| Dharmarajan, Subramanian; Gurel, Zafer; Wang, Shoujian et al. (2014) Bone morphogenetic protein 7 regulates reactive gliosis in retinal astrocytes and Müller glia. Mol Vis 20:1085-108 |
| Shin, Eui Seok; Huang, Qiong; Gurel, Zafer et al. (2014) High glucose alters retinal astrocytes phenotype through increased production of inflammatory cytokines and oxidative stress. PLoS One 9:e103148 |
| Shin, Eui Seok; Sorenson, Christine M; Sheibani, Nader (2014) PEDF expression regulates the proangiogenic and proinflammatory phenotype of the lung endothelium. Am J Physiol Lung Cell Mol Physiol 306:L620-34 |
| Fei, Ping; Zaitoun, Ismail; Farnoodian, Mitra et al. (2014) Expression of thrombospondin-1 modulates the angioinflammatory phenotype of choroidal endothelial cells. PLoS One 9:e116423 |
| Shin, Eui Seok; Sorenson, Christine M; Sheibani, Nader (2014) Diabetes and retinal vascular dysfunction. J Ophthalmic Vis Res 9:362-73 |
Showing the most recent 10 out of 13 publications
