Technologies for imaging the retina in animal models and patients have been significantly improved through advances in instrumentation, enabling high-resolution imaging of tissue structure. Furthermore, decades of basic and clinical research have identified a number of molecular biomarkers which may be valuable for assessing susceptibility to retinal disease, early disease, and disease progression, as well as dissecting molecular mechanisms in preclinical studies. The goal of this proposal is to build upon advances in imaging instrumentation and biomarker research in order to develop technologies for in vivo molecular imaging of the retina. The strategy is based on hairpin functionalized gold nanoparticles (hAuNP), biocompatible gold colloids engineered to enter living tissues and fluoresce upon hybridization with targeted messenger RNA (mRNA) or microRNA sequences. Recently published and preliminary studies demonstrate that hAuNP are capable of specifically targeting multiple distinct RNA sequences in mammalian cells and the retinal vasculature, without adverse effects on cell function. In this proposal, hAuNP will be utilized to validate mRNAs and microRNAs as biomarkers of choroidal neovascularization (CNV), using a mouse model of laser- induced choroidal neovascularization (LCNV).
In Aim 1, hAuNP will be used to image CNV-relevant biomarkers in primary choroidal endothelial cells and retinal pigment epithelial cells, and the biodistribution and safety profiles of hAuNP will be further tested in mouse models.
In Aims 2 and 3 of the proposal, hAuNP will be evaluated in a mouse model of LCNV in order to establish the utility of longitudinal, multiplexed RNA imaging. These studies will set the framework for molecular imaging of RNA and other molecular biomarkers in animal models, and will facilitate clinical translation of these technologies for early detection and staging of disease in patients.

Public Health Relevance

Early detection of neovascularization in AMD is critical for preserving vision, since choroidal neovascularization (CNV) is a key blinding complication in AMD patients. In this proposal, molecular biomarkers of subclinical and/or early CNV will be detected using fluorescent nanoparticles. This work is clinically translational and will eventually enable the clinician to begin treatment earlier, when it can be more effective.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY023397-02
Application #
8620660
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Shen, Grace L
Project Start
2013-03-01
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$382,085
Indirect Cost
$137,085
Name
Vanderbilt University Medical Center
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Zhou, Qinbo; Anderson, Chastain; Zhang, Hongmei et al. (2014) Repression of choroidal neovascularization through actin cytoskeleton pathways by microRNA-24. Mol Ther 22:378-89
Gordon, Andrew Y; Jayagopal, Ashwath (2014) Engineering of Nanoscale Contrast Agents for Optical Coherence Tomography. J Nanomed Nanotechnol Suppl 5:004