Proteins in perfused and non-perfused areas of the trabecular meshwork: potential drug candidates
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Purpose: The etiology of glaucoma is yet unknown. Elevated intraocular pressure (IOP) is a distinct marker
of disease progression, and current treatments aim to decrease IOP in order to slow disease progression. The trabecular meshwork (TM) is responsible for maintaining homeostatic IOP, with the deep tissue of the juxtacanalicular connective tissue (JCT) of the TM being most critical. However, the specific molecular components within the TM have yet to be determined.
Methods: Here, we label anterior segments in perfusion organ culture to identify, quantify, and separate high-(HF) and low-flow (LF) regions of the TM. Multiple fluorescent labels, perfusion times, and pressures are
compared. Quantitative proteomics of HF and LF TM regions, performed to identify select groups of extracellular
matrix (ECM) proteins and pathways, is used here to identify potential targets and pathways for future treatments. Immunofluorescence and quantitative PCR is used to further investigate these potential targets in TM tissues.
Results: Segmental regions are shown to be relatively stable over time. Among the potential therapeutic
candidates identified by quantitative proteomics is decorin, which can induce autophagy in the presence of PEG3. Here we show that PEG3 was expressed in the TM in both HF and LF regions. Integrin alpha 7 (ITGA7), another potential therapeutic target upstream of integrin-like kinase (ILK), was found to be expressed in the JCT region of the TM. Other potential targets, including thrombospondin 1 (THBS1) and components of the TGFβ, P53, Wnt, and integrin signaling pathways are already being tested in animal models.
Conclusions: Although most current treatments decrease IOP, they are unlikely to address the underlying cause of glaucoma. Through our work identifying differences in segmental regions of the TM, we have identified a number of potentially therapeutic proteins and pathways. As our understanding of the major molecular players in IOP maintenance increases, novel treatments may become apparent.
Glaucoma Research 2018-2020, pp. 191-203 #14
Edited by: John R. Samples and Paul A. Knepper
© Kugler Publications, Amsterdam, The Netherlands
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