Research – Nair Lab
The main goal of our laboratory is to identify and characterize genetic factors contributing to ocular diseases with a major focus on glaucoma. Glaucoma is a group of diseases that leads to progressive degeneration of the optic nerve and loss of retinal ganglion cell (RGC) bodies in the retina. It is a leading cause of irreversible blindness. The current knowledge on glaucoma causing genes is limited. This is mainly because glaucoma is primarily a complex multigenic disease. This makes it challenging to identify glaucoma relevant genes and prove their direct involvement in disease causation. To help determine these genetic factors, we utilize various murine models that serve as a powerful tool to identify/validate glaucoma causing genes and provide mechanistic insights into disease pathogenesis.
Our studies integrate two complementary approaches. In the first approach, we investigate how various human candidate genes/pathways (emerging from human linkage or genome-wide association studies) contribute to glaucoma relevant conditions using the mouse. This is mainly achieved by creating genetically modified mice in which the mouse equivalent of the implicated human gene is altered. In a complementary yet synergistic approach, findings from our mouse models of glaucoma are extrapolated to understanding the human disease. Mouse genetics driven experiments along with gene expression analysis in established murine glaucoma models are used to gain insight into the genes/pathways contributing to high intraocular pressure (IOP, a major risk factor for glaucoma) and glaucomatous neurodegeneration. Thereafter, the relevance of the data obtained in mice is extended to human glaucoma by using tools of comparative genetics/genomics.
Our experience in employing the mouse to dissect complex genetic diseases puts us in a unique position to identify and functionally elucidate the role of glaucoma causing genes at a mechanistic level. We utilize a multi-disciplinary approach by integrating the use of genetics, genomics, molecular biology, cell-biology and physiology based experiments in our research.
The various ongoing projects are the following:
- Elucidate the molecular and cellular mechanisms of angle closure glaucoma.
Angle-closure glaucoma (ACG) is a severe subset of glaucoma affecting 16 million people worldwide. It causes blindness in proportionately more people than any other forms of glaucoma. However, very little is known about the genes and the molecular mechanisms contributing to this disease. In ACG, the iris is pushed against the trabecular meshwork (TM), an important ocular drainage structure. This contributes to obstruction of aqueous humor outflow and to the elevation of IOP. The mechanisms of IOP elevation are however more complicated than simple blockage by the iris. Contributions from multiple anatomical and physiological factors are thought to participate in the pathogenesis of ACG. We have recently characterized a mutant mouse with cardinal features of human ACG (including decreased ocular axial length, iris apposition to the trabecular meshwork and high IOP). The causal mutation is in a novel serine protease gene, Prss56. Interestingly, ACG patients with reduced ocular posterior segment length also harbored mutations in PRSS56, thus making our model highly relevant to the human disease. Thus, we are utilizing our mouse model to gain a better understanding of human ACG relevant phenotypes at a mechanistic level.
- Molecular mechanisms contributing to ocular growth and refractive development
Ocular growth is a highly coordinated process geared towards the development of an ideal refractive state, referred to as emmetropia that allow for proper image focusing on the retina. When ocular length does not match the optical focal length, the focused image either falls at a point in front (myopia/nearsightedness) or beyond (hyperopia/farsightedness) the retina. A complex interplay between genetic and environmental factors control emmetropization and ocular growth. The precise mechanism(s) governing these processes, however, remain(s) elusive. Retinal signals are thought to be important for refractive development. Mouse carrying mutation in Prss56, a gene expressed in the retina exhibits reduced axial length and hyperopia. The availability of such a model allows investigating factors participating in the ocular growth and refractive development. Using high throughput gene expression analysis comparing wild-type and Prss56 mutant retinas, we have identified candidate genes/pathways contributing to the regulation of ocular growth/refraction and are investigating their role in the regulation of ocular growth and refraction.
- Risk factors contributing to glaucoma
In recent years, there has been a significant rise in the prevalence of myopia worldwide. This increase has been mainly attributed to changes in life-style including the increased near work (computer-related work, video games etc.) and reduced outdoor exposure. Although most common forms of myopia can be corrected using suitable lenses, myopia constitutes a significant risk factor for more devastating blinding diseases including retinal degeneration and glaucoma. The current views on the relationship between myopia and glaucoma are largely speculative. We are developing a mouse model that recapitulates features of myopia-induced glaucoma. This important resource will allow highly controlled experiments to causally implicate myopia as a factor contributing to glaucoma. Importantly, this mouse model will provide the platform to investigate the role of genetic factors and physiological mechanisms contributing to glaucoma susceptibility in the context of myopia. To this end, we are collaborating with human geneticists to uncover genes contributing to glaucoma in the context of myopia.