Pathogenesis of choroidal neovascularization

Project: Research project

Description

DESCRIPTION (provided by applicant): 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.
StatusFinished
Effective start/end date9/30/048/31/08

Funding

  • National Institutes of Health: $396,250.00
  • National Institutes of Health: $25,271.00
  • National Institutes of Health: $361,667.00
  • National Institutes of Health: $387,475.00

Fingerprint

Choroidal Neovascularization
Extracellular Matrix
Macular Degeneration
Sirolimus
Vascular Endothelial Growth Factor A
Blood Vessels
Vascular Endothelial Growth Factor Receptor-1

ASJC

  • Medicine(all)