The long-term goals are to understand the mechanisms of regulation of fluid flow through the extracellular matrix (ECM) of the trabecular meshwork (TM) and to eventually use this knowledge to develop effective therapies for preventing primary open angle glaucoma (POAG) progression. The immediate goal of this competing renewal project is to test hypotheses about the molecular mechanisms by which TM cells sense the fluid flow fluctuations in the ECM and by which the sensation is transduced to change cell shape and motility to increase or decrease TM pore size, thus regulating the passing of fluid through TM. In particular, we focus on cochlin, a secreted ECM protein, because mass spectrometric analyses have identified cochlin exclusively in human glaucomatous TM but not in normal TM. We have shown in vitro that cochlin undergoes aggregate formation and multimerization when subjected to fluid shear fluctuations indicating that cochlin is capable of mechanosensing. Our organizing hypothesis is that cochlin mechanosensing, in glaucomatous TM, communicates with transmembrane proteins to modulate TM cell shape and motility leading to dysregulation of fluid flow in ECM. Thus, cochlin plays a key role in intraocular pressure (IOP) elevation.
Aim 1 is to test the hypothesis that aberrant cochlin over-expression occurs at the onset of IOP dysregulation. We will determine real time cochlin and TREK-1 levels and dysregulation of IOP (early and continuous abnormal rise in IOP) across different ages in live glaucomatous DBA/2J mice and compare with control DBA/2J-Gpnmb+/SjJ mice using newly developed reagent-based spectral (SD) and magnetomotive (MM) optical coherence tomography (OCT).
Aim 2 is to test the hypothesis that the cochlin mechanosensing signal is transduced via interaction with transmembrane proteins (such as TREK-1), leading to the cytoskeleton changes that modulates fluid flow across the TM filter.
Aim 3 is to test the hypothesis that chronic aberrant expression of cochlin is regulated by a set of transcription factors (Barx2, Nrf2 and Brn3a). We will use primary TM cells, cadaver TM tissues and DBA/2J mice to determine the relative levels of transcription factors (that are responsive to pressure/stretch cycles) whose level modulation is accompanied with cochlin overexpression. Cochlin is the first molecule mechanistically linked to mechanosensing of fluid shear change in the ECM of TM. Establishing this protein's function in aberrant aqueous outflow regulation has great significance for understanding IOP regulation, POAG pathogenesis, and potential intervention strategies.
The proposed research focuses on the mechanisms by which trabecular meshwork (TM) cells in the eye sense the fluid flow fluctuations in the extracellular matrix (ECM) and how they transduce the sensation to respond against fluid shear changes. The outcomes of this research will expand our understanding of the mechanisms of regulation of fluid flow in the TM, and thus of the pressure in the eye, and will eventually enable the developing of effective therapies for glaucoma progression.
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