Dysregulation of the Acetylome in Age-Related Macular Degeneration
We are just beginning to gain scientific insight into the power of epigenetic modifications on genome-wide transcription. In this project, we plan to study a highly significant role for histone deacetylase function in retinal pigment epithelial cell gene expression profiles and cell death in dry age-related macular degeneration (AMD). These data will provide important molecular insights to enhance our knowledge of the complex intersection of aging biology, epigenetics and inflammation.
We are just beginning to gain scientific insight into the power of epigenetic modifications on inflammatory gene expression that occurs during biologic aging. The goal of this project is to utilize CRISPR/Cas9 gene editing to study epigenetic signatures in experimental models of age-related macular degeneration (AMD).
In the first year of the award, I will rigorously evaluate CRISPR/Cas9 related cytotoxicity and immune activation in the retinal pigment epithelium (RPE) in experimental models. These safety and off-target data are critical to the future use of the CRISPR/Cas9 system in additional studies targeting epigenetic pathways and for the translation of this powerful gene-editing technology to the treatment of retinal degenerative diseases.
Histone deacetylases (HDAC) are a critical family of enzymes which are dysregulated in the RPE in AMD. In the second year of the award, I will apply CRISPR/Cas9 gene-editing techniques to develop experimental models of HDAC deficiency in the RPE. The effects of HDAC deficiency on cellular viability, regulation of inflammatory gene expression, and specific signatures of acetyl-histone marks will be studied to provide the ground-work for improving our understanding of this epigenetic pathway in the RPE.
Epigenetic derangements have been implicated as important pathobiologic mechanisms in numerous age-related diseases. Still, there is extremely limited knowledge about the role of histone acetylation during AMD. I have recently discovered that enzymatic components that regulate the acetylome are altered in AMD, and that there is increased acetylation in the aging RPE. The proposed research will provide critical novel insights into the dysregulation of this cellular pathway, and its effects on inflammatory gene expression and degeneration in the aging retina utilizing CRISPR/Cas9 gene-editing technology.
Currently, there is no effective treatment for the prevention, reversal or stabilization of dry AMD. While there have been tremendous scientific advancements to elucidate the pathogenesis of this blinding disease, there has been no translation of a targeted therapeutic that arrests RPE cell death. I have discovered that imbalances in the acetylome in the RPE induce an inflammatory gene expression profile similar to AMD, and resulted in RPE cell death and atrophy. Given the upstream location of this pathway, it would be highly suitable to use the results to pharmacologically target and rebalance gene expression to reduce inflammation and prevent AMD progression.
About the Researcher
Throughout my medical and post-doctoral education, I have been deeply fascinated by the fields of vascular and aging biology, microsurgery, and biomedical technology. I have embraced the profession of vitreoretinal surgery, an art that wholly encompasses all of these interests. My career goals are to obtain mastery of the diagnosis and treatment of vitreoretinal disease and to combine my expertise in the basic and clinical sciences to advance the understanding of vascular and aging diseases of the eye. My research is focused on developing models of epigenetic regulation of inflammation in aging diseases of the retina. Currently, most scientific understanding of epigenetic biology is in the field of development and cancer. In my early career period, I have been investigating various pathways of pro-inflammatory signaling in the retina and have recently discovered a powerful ability for biochemical modification of histones, a protein that complexes with DNA to form the nucleosome, to regulate the expression of specific inflammatory factors found in AMD. With this solid foundation in the biomedical sciences, I plan to rigorously dissect the molecular mechanisms of this pathway to determine the role and effects of histone modification in the healthy and diseased retina.
In our approach to modern medical education, there has never been a time that has required a more robust grasp of basic scientific principles in order to interpret the flood of research from around the world. This is especially apparent in ophthalmology, which has historically been graced by leaders with expertise in the physical and biologic sciences, a benefit that has advanced this field considerably. My philosophy is that by supporting the dedicated training of clinician-scientists, we will close this information gap to allow the translation of feasible and effective therapies and provide a clear channel between the clinic and the laboratory. The epidemic of AMD is a perfect test for this challenge. The reality is, each day I see so many patients that I am unable to help, and this drives me in my race for a cure. It is through the generous support of the BrightFocus Foundation and its' donors that I will be able to conduct my scientific investigations into epigenetic signatures in AMD, with the hope that this work will seed the foundation for a novel approach to treating this blinding disease in the future.
First published on: November 14, 2018
Last modified on: June 2, 2020