Browsing by Subject "Trabecular Meshwork"
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Item Open Access Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity.(The Journal of clinical investigation, 2016-07) Souma, Tomokazu; Tompson, Stuart W; Thomson, Benjamin R; Siggs, Owen M; Kizhatil, Krishnakumar; Yamaguchi, Shinji; Feng, Liang; Limviphuvadh, Vachiranee; Whisenhunt, Kristina N; Maurer-Stroh, Sebastian; Yanovitch, Tammy L; Kalaydjieva, Luba; Azmanov, Dimitar N; Finzi, Simone; Mauri, Lucia; Javadiyan, Shahrbanou; Souzeau, Emmanuelle; Zhou, Tiger; Hewitt, Alex W; Kloss, Bethany; Burdon, Kathryn P; Mackey, David A; Allen, Keri F; Ruddle, Jonathan B; Lim, Sing-Hui; Rozen, Steve; Tran-Viet, Khanh-Nhat; Liu, Xiaorong; John, Simon; Wiggs, Janey L; Pasutto, Francesca; Craig, Jamie E; Jin, Jing; Quaggin, Susan E; Young, Terri LPrimary congenital glaucoma (PCG) is a devastating eye disease and an important cause of childhood blindness worldwide. In PCG, defects in the anterior chamber aqueous humor outflow structures of the eye result in elevated intraocular pressure (IOP); however, the genes and molecular mechanisms involved in the etiology of these defects have not been fully characterized. Previously, we observed PCG-like phenotypes in transgenic mice that lack functional angiopoietin-TEK signaling. Herein, we identified rare TEK variants in 10 of 189 unrelated PCG families and demonstrated that each mutation results in haploinsufficiency due to protein loss of function. Multiple cellular mechanisms were responsible for the loss of protein function resulting from individual TEK variants, including an absence of normal protein production, protein aggregate formation, enhanced proteasomal degradation, altered subcellular localization, and reduced responsiveness to ligand stimulation. Further, in mice, hemizygosity for Tek led to the formation of severely hypomorphic Schlemm's canal and trabecular meshwork, as well as elevated IOP, demonstrating that anterior chamber vascular development is sensitive to Tek gene dosage and the resulting decrease in angiopoietin-TEK signaling. Collectively, these results identify TEK mutations in patients with PCG that likely underlie disease and are transmitted in an autosomal dominant pattern with variable expressivity.Item Open Access Micro-Viscoelastic Properties of the Human Conventional Outflow Pathway and Their Evolution in an Early Ocular-Hypertension Model.(2021) Shah, Tejank PragneshPrimary OAG (POAG) is the second leading cause of irreversible blindness in the US and its prevalence is expected to worsen in the coming years. Major pathological changes have been attributed to the Juxtacanicular Tissue (JCT) and Inner Wall (IW) of Schlemm’s Canal (SC) within the human conventional outflow pathway. Biological tissues like the JCT/IW are viscoelastic in nature with both intra-cellular and extra-cellular mechanisms by which to store and dissipate applied forces. How these events contribute towards regulation of the local mechanobiology in the dynamic reciprocitybetween cells, their extracellular matrix (ECM), and in ultimately regulating outflow resistance, is poorly understood. Furthermore, the viscoelastic properties of the human trabecular meshwork (hTM) tissue are poorly understood. As a first step to develop more insight into the role of viscoelasticity, it was our goal to determine the localized dynamic mechanical properties of different regions of the hTM as a function of dexamethasone treatment. To explore the viscoelastic properties of the different tissue regions in the hTM comprising the hTM, we applied our co-located AFM-based rheometer/CLSM method to frontal sections of hTM under control and early ocular hypertensive conditions across a broad frequency range (1 Hz-1 kHz). We specifically considered the storage and loss moduli in the ocular pulse-relevant frequency range (1-10 Hz) and their changes across regions under dex treatment for two donors.
Item Open Access The Relationship of Trabecular Meshwork Stiffness and Outflow Function(2013) Camras, LucindaThe trabecular meshwork (TM) is comparable to a bioactive filter that plays a major role in regulating outflow of aqueous humor of the eye and setting intraocular pressure (IOP). TM dysfunction may lead to ocular hypertension which is the major risk factor in glaucoma. Although the outflow properties of the TM have been assessed over the last sixty years, very little work has been done assessing its mechanical properties. Therefore, the major goals of these studies were two-fold: (1) to determine the relationship between mechanical properties of TM, specifically the bulk Young's modulus, and outflow function in normal and glaucomatous eyes, and (2) to establish a method and possible animal model for future testing of this relationship.
Outflow function was assessed by constant pressure perfusion in enucleated eyes at four pressure levels (10, 20, 30, and 40 mmHg) to determine outflow facilities and variability in outflow resistance with pressure elevation. A micro-strain analyzer (MSA) was used to determine the circumferential bulk Young's modulus of the TM post-perfusion. Based on their relative ease of availability, pigs and rats were explored as possible animal models. Due to the small size of rat eyes, atomic force microscopy (AFM) was used to assess the Young's modulus of TM rather than with a MSA.
We found that there was a relationship with better outflow function and a stiffer TM in normal eyes. Additionally, glaucomatous TM was found to be much softer and more variable than normal TM. Unfortunately, porcine TM did not serve as a good model for the bulk Young's modulus of human TM, presumably due to anatomical difference in its outflow pathway. Lastly, we were able to establish a new method for measuring the Young's modulus of rat TM for future work to determine potential mechanism for evaluating stiffness changes that may be associated with glaucoma.