Lysophosphatidic Acid Induces ECM Production via Activation of the Mechanosensitive YAP/TAZ Transcriptional Pathway in Trabecular Meshwork Cells.

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2018-04

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Abstract

Lysophosphatidic acid (LPA), a bioactive lipid, has been shown to increase resistance to aqueous humor outflow (AH) through the trabecular meshwork (TM). The molecular basis for this response of the TM to LPA, however, is not completely understood. In this study, we explored the possible involvement of mechanosensitive Yes-associated protein (YAP) and its paralog, transcriptional coactivator with PDZ-binding domain (TAZ), transcriptional activation in extracellular matrix (ECM) production by LPA-induced contractile activity in human TM cells (HTM).The responsiveness of genes encoding LPA receptors (LPARs), LPA hydrolyzing lipid phosphate phosphatases (LPPs), and the LPA-generating autotaxin (ATX) to cyclic mechanical stretch in HTM cells, was evaluated by RT-quantitative (q)PCR. The effects of LPA and LPA receptor antagonists on actomyosin contractile activity, activation of YAP/TAZ, and levels of connective tissue growth factor (CTGF), and Cyr61 and ECM proteins in HTM cells were determined by immunoblotting, mass spectrometry, and immunofluorescence analyses.Cyclic mechanical stretch significantly increased the expression of several types of LPARs, LPP1, and ATX in HTM cells. LPA and LPA receptor-dependent contractile activity led to increases in both, the protein levels and activation of YAP/TAZ, and increased the levels of CTGF, Cyr61, α-smooth muscle actin (α-SMA), and ECM proteins in HTM cells.The results of this study reveal that LPA and its receptors stimulate YAP/TAZ transcriptional activity in HTM cells by modulating cellular contractile tension, and augment expression of CTGF that in turn leads to increased production of ECM. Therefore, YAP/TAZ-induced increases in CTGF and ECM production could be an important molecular mechanism underlying LPA-induced resistance to AH outflow and ocular hypertension.

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10.1167/iovs.17-23702

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Ho, Leona TY, Nikolai Skiba, Christoph Ullmer and Ponugoti Vasantha Rao (2018). Lysophosphatidic Acid Induces ECM Production via Activation of the Mechanosensitive YAP/TAZ Transcriptional Pathway in Trabecular Meshwork Cells. Investigative ophthalmology & visual science, 59(5). pp. 1969–1984. 10.1167/iovs.17-23702 Retrieved from https://hdl.handle.net/10161/17216.

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Scholars@Duke

Skiba

Nikolai Petrovich Skiba

Associate Professor of Ophthalmology

My research focuses on applying mass spectrometry based proteomics to study proteins in eye tissues, cells and sub-cellular compartments to understand mechanisms of vision. An important aspect of my research is to identify proteins in different compartments of retinal photoreceptor cells, their amount and modification status at different cell states defined by the light conditions, genotype, disease etc. This information can be valuable in understanding molecular mechanisms of vision and biology of the photoreceptor cell. Another important aspect of my research is to assist basic scientist and clinicians in our department in their proteomic needs which include identification of proteins and other biomolecules in a given biological sample, detection of protein post-translational modifications and sequence variations, elucidation of protein-protein interactions and also characterization of changes in the protein concentration and composition in a biological sample at different conditions.

Rao

Ponugoti Vasantha Rao

Richard and Kit Barkhouser Distinguished Professor

Research in our laboratory focuses on two areas of ocular diseases- cataract and glaucoma.

As it relates to lens biology, we are investigating cytoskeletal signaling pathways critical for lens development, cytoarchitecture, shape and function. Ongoing studies are focused on identification and characterization of plasma membrane cytoskeletal scaffolding proteins (e.g. Periaxin, ankyrins and dystrophin/dystroglycan) involved in regulation of lens fiber cell shape, alignment, tensile properties, membrane domain organization and channel protein activity, and to determine how dysregulation of membrane cytoskeletal scaffolding activity impacts these determinants of lens structure and function. Our studies are based on using both in vitro and in vivo models, and application of high resolution microscopy, mass spectrometry, biochemical and gene targeting approaches.

In the context of glaucoma, we are exploring the cellular and molecular mechanisms involved in homeostasis of intraocular pressure and aqueous humor drainage with the ultimate goal of identifying novel molecular targets upon which to base the design of therapeutic glaucoma treatments.  Our laboratory is currently studying the extracellular and intracellular mechanisms (e.g. GDF-15, extracellular kinases and phosphatases, Rho GTPase/Rho kinase and the Autotaxin-LPA axis) that control cell morphology, cell adhesive interactions, plasticity, transdifferentiation, extracellular matrix synthesis, phosphorylation and organization, fibrosis and contractile properties of the trabecular meshwork, and aqueous humor outflow and intraocular pressure. These studies utilize both in vitro and in vivo models, and a combination of trabecular meshwork-derived primary cultures, perfusion studies, high resolution microscopy, mass spectrometry, biochemical, physiological and gene targeting approaches.


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