Transgenic Brown Norway Rats for Glaucoma Research
Glaucoma is the world’s leading cause of irreversible blindness. This BrightFocus Foundation research grant will apply new technologies to make live Brown Norway rat models in the lab that express human genes that lead the rats to develop human-like forms of glaucoma. “Humanized” rat models generated by this project will be used by eye researchers to find new therapies that specifically neutralize the human glaucoma-causing genes, thereby preventing glaucoma in the rats. Therapies that prevent glaucoma from developing in the humanized rat glaucoma models will provide candidate therapeutics for battling glaucoma in humans.
Our BrightFocus Foundation project will generate novel visual systems for inventing new glaucoma medicines by genetically engineering a special rat strain (ie, Brown Norway) so that their eyes express clinically relevant, heritable human glaucoma-causing genes.
The Brown Norway rat strain is becoming increasingly instrumental in glaucoma research due to the anatomic similarity between their eyes and human eyes, as well as how finely their eyes can be manipulated in procedures used to experimentally and pharmacologically regulate intraocular pressure (IOP) to induce glaucoma. Thus, our project will open new doors for scientists to investigate how actual human gene mutations impact glaucoma susceptibility under highly controllable physiological conditions within the eyes of Brown Norway rats.
As a primary example, to model a pervasive, heritable form of human glaucoma we will generate transgenic Brown Norway rats that express a mutant form of the human “myocilin” gene, termed MYOCY437H, in their eyes. Brown Norway rats that inherit human MYOCY437H will allow glaucoma researchers to investigate genetic, biochemical and biomechanical mechanisms that elicit glaucoma-causing pathological responses to the abnormal MYOCY437H protein in trabecular meshwork cells (TM cells), which ends up disrupting the flow of fluid from aqueous humor out of the eye. Build-up of fluid within the eye, caused by malfunctioning TM cells, increases IOP, and over time, elevated IOP leads to glaucoma susceptibility by damaging retinal nerve cells required for vision. For the first time, our project will provide transgenic Brown Norway rat models that will be useful for establishing simple diagnostics for testing new glaucoma medicines in vivo, including next-generation therapeutics that act on TM cells to restore normal IOP.
Despite enormous potential for fast-tracking glaucoma research, to date, due to previous technical hurdles, Brown Norway rats have yet to be genetically modified with human DNA that causes glaucoma. Therefore, our project is highly unique in that it will apply ground-breaking sperm stem cell genome editing technologies to enable our laboratory to generate genetically humanized Brown Norway rat models in the fight against glaucoma. In doing so, our BrightFocus Foundation project will open new doors for scientists to investigate how distinct human glaucoma susceptibility gene mutations identified in different human populations impact both vision loss and the efficacy of highly specialized glaucoma therapeutics.
About the Researcher
The principal investigator, Dr. Kent Hamra, is a leading expert on the biology and applications of sperm stem cells in the Department of Obstetrics and Gynecology, and Cecil H. and Ida Green Center for Reproductive Biology Sciences, at the University of Texas Southwestern Medical Center in Dallas. Dr. Hamra’s research emphasis is on establishing spermiogenetic technologies that will facilitate the translation of research aimed at clinically regulating and curing disease processes.
Dr. Hamra’s science background stems from his pre-doctoral training with Dr. Mark G. Currie at Monsanto Co. Research, where they worked to discover and develop new drugs that block inflammation, reduce blood pressure and control intestinal function. Dr. Hamra earned his PhD in pharmacology at the University of Missouri-Columbia with Dr. Leonard R. Forte, where they discovered and elucidated the structure of Uroguanylin (Guca2B) as a peptide hormone that regulates fluid and metabolite transport by cells. Drugs that modulate Uroguanylin activity are currently being developed to target disease processes in gastrointestinal, renal/cardiovascular, pulmonary and neurological systems.
Dr. Hamra conducted his postdoctoral training in Dr. David L. Garbers’ laboratory at the University of Texas Southwestern Medical Center in Dallas, where he invented methods to culture rat spermatogonial stem cells (ie, sperm stem cells), prior to starting his own lab and inventing what are currently the most robust conditions for culturing and genetically modifying rat spermatogonial stem cells. Dr. Hamra’s work on spermatogonial biology and spermiogenetic technologies provided the foundation for his numerous peer-reviewed publications, patents, national and international presentations, invitations to serve on NIH scientific advisory boards and commercialization of NIH-sponsored research.
My dedication to advancing sperm stem cell technologies is fueled by its immense untapped potential to benefit a broad spectrum of biomedical research fields and scientists’ collective efforts to make discoveries that improve health and save lives. The exceptionally high-impact science supported by the BrightFocus Foundation is a most wonderful and remarkable gift to humanity. We were immediately struck by the mission put forth by BrightFocus Foundation donors to help people with degenerative diseases, plus how the biomedical potential of our research so nicely aligns with their goal of improving the health and well-being of people with neurodegenerative diseases. We applaud the BrightFocus Foundation’s driving force that is empowering scientists to conduct state-of-the-art research and development projects critical for designing safer, more efficacious and personalized therapeutics that will heal people with glaucoma and many other neurodegenerative diseases.
First published on: July 27, 2018
Last modified on: May 28, 2020