The long-term objectives are to understand the pathogenesis of CNV (choroidal neovascularization) in AMD (age-related macular degeneration) and to search for suitable treatments. AMD is the leading cause of blindness in the population over 65 years old. Exudative AMD, characterized by CNV, causes severe loss of vision. Options of treatments are limited for those with exudative AMD. Development of new treatments is hindered by the poor understanding of pathogenesis of CNV in AMD, and the lack of suitable animal models. As the senior population continues to expand rapidly, the situation is reaching epidemic proportions. ? ? This proposal focuses on the pathogenesis of CNV.
Four Specific Aims are proposed to study the roles of ECM (extracellular matrix) deposits, VEGF (vascular endothelial growth factor), and mTOR (mammalian target of rapamycin) in CNV development. Abnormal ECM deposits are commonly found in AMD with CNV, but their roles in CNV development are not clear. Several new techniques will be used to create artificial ECM deposits in the subretinal space of experimental rats, to induce CNV, and to visualize blood vessels. The first Specific Aim will attempt to establish a causal relation between ECM deposits and CNV. New blood vessels induced by ECM deposits from the choroid will be identified, which would support the causal relation. Positive results have been observed in preliminary studies. The second will test a hypothesis that the space and microenvironment provided by ECM deposits facilitate the spread of CNV. Subretinal deposits will be created using ECM and non-ECM materials. Degrees of CNV in samples will be measured as a CNV indexes and digital CNV volume. Significantly higher CNV indexes or volume in ECM deposits would support the hypothesis. The third Specific Aim will test a hypothesis that VEGF is essential for CNV development. Two VEGF inhibitors, a soluble VEGFR-1 and a VEGF antibody, will be used to block the interaction between VEGF and its receptors. Positive results should confirm the role of VEGF in CNV. The last Specific Aim will attempt to establish a role of mTOR in CNV development; mTOR inhibitor rapamycin will be used. Complete inhibition of CNV by rapamycin has been observed in preliminary studies. ? ? Data from these experiments would not only shed light on the roles of ECM deposits, VEGF, and mTOR in CNV pathogenesis, but also provide basis for developing new strategies to control CNV in AMD. ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY015289-01A1
Application #
6821836
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Dudley, Peter A
Project Start
2004-09-30
Project End
2007-08-31
Budget Start
2004-09-30
Budget End
2005-08-31
Support Year
1
Fiscal Year
2004
Total Cost
$387,475
Indirect Cost
Name
University of Pennsylvania
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Lu, Jianmin; Luo, Lingyu; Huang, Deqiang et al. (2018) Photoreceptor Protection by Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF). eNeuro 5:
Li, Yiwen; Huang, Deqiang; Xia, Xin et al. (2012) What is the role of CCR3 in choroidal neovascularization? Adv Exp Med Biol 723:279-84
Wen, Rong; Tao, Weng; Luo, Lingyu et al. (2012) Regeneration of cone outer segments induced by CNTF. Adv Exp Med Biol 723:93-9
Li, Yiwen; Huang, Deqiang; Xia, Xin et al. (2011) CCR3 and choroidal neovascularization. PLoS One 6:e17106
Li, Yiwen; Tao, Weng; Luo, Lingyu et al. (2010) CNTF induces regeneration of cone outer segments in a rat model of retinal degeneration. PLoS One 5:e9495
Cao, Jingtai; Zhao, Lian; Li, Yiwen et al. (2010) A subretinal matrigel rat choroidal neovascularization (CNV) model and inhibition of CNV and associated inflammation and fibrosis by VEGF trap. Invest Ophthalmol Vis Sci 51:6009-17
Tao, Rong; Gong, Jun; Luo, Xixi et al. (2010) AMPK exerts dual regulatory effects on the PI3K pathway. J Mol Signal 5:1
Wen, Rong; Song, Ying; Liu, Yun et al. (2008) CNTF negatively regulates the phototransduction machinery in rod photoreceptors: implication for light-induced photostasis plasticity. Adv Exp Med Biol 613:407-13
Li, Yiwen; Song, Ying; Zhao, Lian et al. (2008) Direct labeling and visualization of blood vessels with lipophilic carbocyanine dye DiI. Nat Protoc 3:1703-8
Zhao, Lian; Wang, Zhenfang; Liu, Yun et al. (2007) Translocation of the retinal pigment epithelium and formation of sub-retinal pigment epithelium deposit induced by subretinal deposit. Mol Vis 13:873-80

Showing the most recent 10 out of 11 publications