Local and Systemic Inflammation in a Mouse Model of RPE Oxidative Damage
Macular degeneration is a leading cause of blindness among the older population of the USA and other developed countries. Inflammation has been linked to age-related macular degeneration (AMD). My research goal is to improve a mouse model of this disease by introducing pro-inflammatory cues, and to experiment with a method of decreasing inflammation in the eye to test the idea that localized control of inflammation could help protect vision. If successful, this method could also be tested in other diseases linked to aging and inflammation, such as Alzheimer’s disease.
The goals of this project are (i) to improve a mouse model of macular degeneration, and (ii) to test a genetically modified virus that can control inflammation within the eye of this mouse model. In the first set of experiments, we will cause a mild inflammation in this mouse model. We will inject these mice with either oxidized proteins, bacterial components, or normal saline in a single injection when they are young. These mice will then be follow using techniques employed by clinicians to evaluate how their retina degenerates as they age. Our hypothesis is that by causing a mild inflammation in these animals, we will be able to induce changes similar to those seen in patients with AMD, because these animals already have a propensity to develop a slow retinal degeneration due to increased oxidative stress in their retinas. In the second set of experiments, we will use a genetically modified virus to deliver a gene known to inhibit inflammation in the eye. We will inject our mouse model with this virus or with a similar virus delivering an irrelevant gene in the opposite eye. These mice will be follow by our group as described in the previous experiments, and we will look for effects that could indicate protection of the retina. We will also use techniques that can tell us whether any of these effects are due to the anti-inflammatory properties of our virus, or due to an unknown function. These experiments are innovative because they seek to improve a mouse model based on current knowledge from human disease, while also testing novel therapies that could be of benefit for affected individuals. Completion of this research project will improve our knowledge of how systemic inflammation could modify the progression of AMD.
About the Researcher
Cristhian J. Ildefonso, PhD, was born in Puerto Rico. He obtained a BSc degree from the University of Puerto Rico in Río Piedras with a double major in biology and chemistry. As a member of the MARC U*STAR Program at the University of Puerto Rico, he studied the effect of opioids on murine macrophages. In 2005, he joined the inaugural class of the new Translational Biology and Molecular Medicine Program at Baylor College of Medicine. Under the mentorship of Drs. Richard L. Hurwitz and Catherine M. Bollard, he characterized the immune response against an adenoviral vector delivered intravitreally in retinoblastoma patients. He also studied the influence of the intraocular environment on viral vector-mediated transgene expression. This work was funded by a National Research Service Award fellowship from the National Institute of General Medical Sciences. After completing his doctoral studies in 2011, Dr. Ildefonso joined the laboratory of Dr. Alfred S. Lewin to conduct his postdoctoral studies. During his tenure in Dr. Lewin’s laboratory, Dr. Ildefonso developed and characterized several anti-inflammatory genes of eukaryotic or viral origin that can be delivered by an AAV vector. He also developed genes and artificial miRNAs that control the NRF2 signaling pathway and therefore promote the expression of antioxidant genes. He tested these vectors in models of ocular diseases, such as uveitis and geographic atrophy. In 2013, he was awarded the ARVO/Genentech AMD Research Fellowship in the AMD Translational Research category. In 2016, Dr. Ildefonso joined the Department of Ophthalmology at the University of Florida as an Assistant Professor and has a joint appointment in the Department of Molecular Genetics & Microbiology of the same Institution. His research focuses on understanding the role of inflammation in retinal degenerative diseases and seeks to target inflammatory pathways in these diseases using gene therapy.
I will always remember the image of my great-grandmother, who spent most of the days I can remember on a bed and moving only with the help of others, due to her severe vision loss. As a child, I could not understand why her doctors could not help her more to recover her vision. This memory spiked my interest in vision research, with the hope that one day I could make a contribution to science that would help alleviate the suffering associated with vision loss. Receiving this award has moved me closer towards the achievement of that goal. I would like to express my gratitude to the BrightFocus Foundation and its donors for supporting my research program. As a junior faculty member, it is important to be able to test novel ideas that can advance our field; however, sometimes it’s difficult to find funding for these ideas and projects. This award will help further the goals of our research group by supporting work that, although an early stage, likely will benefit the field as a whole and could lead to new therapies.
First published on: August 1, 2017
Last modified on: September 30, 2019