Project: C02

The lymphatic regulator SVEP1 in Schlemm´s canal function – a therapeutic target for glaucoma

The Schlemm’s canal (SC) controls intraocular pressure (IOP) by drainage of the aqueous humor from the eye. Increased resistance to aqueous humor outflow through this system raises IOP and causes glaucoma. IOP is the main risk factor of glaucoma development and progression. Glaucoma is a leading cause of blindness. Our understanding of the pathophysiological changes of IOP increase is scarce. Hence, there is an unmet need for new treatment options to lower IOP.

To date, it is unknown which changes in SC function cause the pathological increase in IOP. It was only recently discovered that the SC consists of a highly organized, unique hybrid vascular structure combining distinct lymphatic and blood vascular endothelial features (‘atypical lymphatic vessel’). The SC itself is covered by trabecular meshwork cells facing the anterior chamber of the eye. However, most glaucoma studies focus on the trabecular meshwork rather than the SC itself. Analysis of the newly discovered lymphatic features of the SC offers a new understanding of the pathophysiology of IOP increase and provides novel treatment options in different forms of glaucoma.

Schlemm’s canal A) depiction of the SC, depicted in green, encircling the cornea and draining the aqueous humor into episcleral & aqueous veins (E&A vein) as well as limbal lymphatic vessels (LV), both depicted in red. B) aqueous humor outflow (AHO) from basal (green cells) to apical (orange cells) side of the SC. The apical side of the SC expresses Prox1, VEGFR3, Tie1, Tie2 and integrinα9, but not Lyve1 or Podoplanin (‘atypical lymphatic vessel’). Impairment of SC function increases IOP and leads to glaucoma. A and B) modified after Petrova and Koh, 201812. C) PECAM-1 staining of the vasculature in the iridocorneal region D) cut-out of the indicated region in C): PECAM-1 staining of z-planes showing the SC in green, PECAM-1 staining of z-planes containing E&A veins and limbal lymphatic vessels in red. E) surface rendering of the SC (green) as well as E&A veins and limbal lymphatic vessels (red) using IMARIS software (own data).

The student will analyse the role of known glaucoma risk factors in relation to SC function. Specifically the will aim to: 1) describe in detail new pre-clinical Svep1+/- and Svep1/Tie2 +/- mouse models for increased IOP, (2) assess correlated protein expression changes in normal and glaucoma human tissue, (3) decipher the mode of action of SVEP1-mediated regulation of TIE-1/-2/ANG signalling, and (4) develop a new therapeutic treatment/prevention option for glaucoma via activation of TIE1/-2 signalling in SC through providing recombinant SVEP1 protein.

Key methods: in vivo transgenic models, morphometric analysis, IF, cell culture assays, FISH, RNA and protein analysis, cell signalling methodologies; pre-clinical testing

CRC1607 | Prof. Dr. med. Verena Prokosch

Project leader

Prof. Dr. med. Verena Prokosch

CRC 1607 | Prof. Dr. rer.-nat. Stefan Schulte-Merker

Project leader

Prof. Dr. rer.-nat. Stefan Schulte-Merker

PostDoc

Dr. Dörte Schulte-Ostermann

PhD Student

Levi Huber

PhD student

Steven Reger

MD Fellow

Anne-Kathrin Wegner