Glaucoma is the leading cause of irreversible blindness affecting more than 70 million people worldwide. This number is projected to increase to nearly 80 million by 2020. It is characterized by progressive degeneration of retinal ganglion cells (RGCs), the projection neurons that carry signals from the inner retina to the brain, and subsequent alterations in the optic nerve head. The biological basis of glaucoma and the factors contributing to its progression are not completely understood. At present, the sole modifiable risk factor for glaucomatous RGC loss is intraocular pressure (IOP). IOP is determined by the continuous generation of aqueous humor and its elimination via the trabecular meshwork (TM). The TM is an avascular, architecturally complex connective tissue. Its degeneration is associated with enhanced extracellular matrix (ECM) deposition and reduced cellularity. Consequently, increased resistance to aqueous humor outflow causes pathological IOP elevation/ocular hypertension. Current treatments of glaucoma aim to lower IOP. Understanding the mechanisms leading to TM cell dysfunction and loss in the glaucomatous eye could help identify novel strategies to target this primary pathological site.
The role of the chemokine CXCL12 in trabecular meshwork cell homeostasis
The chemokine CXCL12, also known as SDF-1, is involved in cell survival, neuromodulation, and ECM adhesion. CXCL12 isoforms are generated by alternative splicing. Further, CXCL12 is proteolytically cleaved at both ends forming truncated derivatives with altered bioactivity. CXCL12 plays a role in myofibroblast-mediated ECM remodeling in pathological conditions. In the eye, CXCL12 and its cognate receptor CXCR4 are expressed in various cells; however, little is known about CXCL12 in the TM.
A primary research focus of our laboratory is the investigation of TM architecture and function. We study the role of CXCL12 in TM cell biology, and its function in mesenchymal stem cell engraftment for therapeutic TM remodeling. We employ a TM organoid system to investigate the effects of CXCL12 splice variants and their natural derivatives on TM architecture. Integration with a microfluidics chip enables engineering of a “TM-on-a chip” platform to perform studies under dynamic flow conditions, and investigating CXCL12-mediated chemoattraction for mesenchymal stem cell therapy of high-pressure glaucoma.
The role of lamina cribrosa biomechanics in glaucoma
The site of retinal ganglion cell (RGC) injury in glaucoma occurs at the lamina cribrosa (LC), a porous collagenous network that provides structural support to RGC axons as they exit the globe. Biomechanical strain on the LC induced by IOP elevation is thought to cause direct mechanical failure of the collagen matrix. In collaboration with Dr. Preethi Ganapathy, we are investigating cellular mechanisms that alter LC biomechanics in response to dynamic IOP fluctuation, and how this affects RGC axon function.