Position title: Assistant Professor
Phone: (608) 265-3996
1300 University Ave
Madison, WI 53706
- McDowell Lab
My research aims to (1) determine the molecular pathway involved in the development of elevated intraocular pressure (IOP) which is the most important risk factor in the development of glaucoma, (2) develop novel mouse models of glaucoma to further advance the field of glaucoma research, and (3) elucidate specific retina ganglion cell (RGC) subtype susceptibility to glaucomatous damage.
- Elevated IOP is one of the primary risk factors in the development of glaucoma. The TM is a critical tissue involved in the outflow of aqueous humor and regulation of IOP. Changes in the ECM environment in the TM can alter the ability of aqueous humor to properly drain from the anterior chamber. The involvement of TGFβ2 signaling pathways in the regulation of the ECM in the TM has been extensively studied. Recent evidence has implicated toll-like receptor 4 (TLR4) in the regulation of ECM and fibrogenesis in other tissues such as liver, kidney, lung and skin, by inhibition of BMP and the activin membrane-bound inhibitor (BAMBI). I propose that the TLR4 signaling pathway is also involved in the regulation of the ECM in the TM. Our hypothesis is endogenous TLR4 ligands, also known as DAMPs (damage associated molecular patterns), activate TLR4 and augment TGFβ2 signaling sensitivity by downregulation of BAMBI, leading to increased ECM production in the TM and increased IOP. We are addressing this hypothesis with both in vitro cell culture, in vivo mouse model methodologies, and ex vivo perfusion organ culture of human donor eyes.
- Recently we identified a novel mouse model of ocular hyptertension. These transgenic animals harbor a constitutively active form of the fibronectin EDA isoform (FN-EDA). FN-EDA is a known DAMP and we hypothesize that the constitutively active EDA causes a persistent fibrogenic feed forward response due to TGFβ2-TLR4 signaling crosstalk, leading to increased ECM in the TM and elevated IOP. We are currently characterizing the TM, retina, and optic nerve phenotypes in this mouse strain. This model would be an invaluable resource for the field for glaucoma research.
- Primary congenital glaucoma (PCG) is a severe form of glaucoma with age of onset from birth to 3 years of age. PCG causes high IOP, death/damage to RGCs and the optic nerve, and can lead to permanent loss of vision. The cellular mechanisms leading to RGC loss and optic nerve damage are unknown. Clinical studies have suggested that certain RGC subpopulations are more susceptible to glaucomatous damage. By identifying the pattern and timing of cell death of RGC subtypes, we can elucidate mechanistic pathways that predispose RGCs and their axons to failure and/or death. Recently a mouse model of congenital glaucoma was discovered. Mutation in the Sh3pxd2b gene (referred to as nee) causes anterior segment dysgenesis, elevated IOP, RGC death, and optic nerve damage. Our hypothesis is PCG phenotypes in nee mice cause RGC subtype specific cell death over time. We aim to identify RGC subtype specific cell death utilizing nee mice and substrains of mice with GFP selectively expressed by individual RGC subtypes. This unique study will help identify different susceptibilities in RGC subtypes to PCG induced cell death and help to determine the pattern and mechanism of cell death/damage leading to visual field defects in PCG.