Faculty Bibliography

BACKGROUND:Routine assessment of photophobia in the clinical setting may underestimate the presence and severity of this condition. We aimed to develop and validate a questionnaire to improve evaluation of the impact of photophobia on activities of daily living, and to determine the relationship of this questionnaire to psychophysical assessment of light sensitivity thresholds. METHODS:We developed the 17-item Utah Photophobia Symptom Impact Scale (UPSIS-17) and compared its psychometric properties to the 8-item Korean Photophobia Questionnaire (KUMC-8). Ninety five subjects with or without light sensitivity completed both questionnaires; 72 also completed laboratory-based assessment of light sensitivity thresholds. We used Rasch analysis to evaluate instrument targeting, including internal consistency and reliability. Correlation analysis was used to assess the relationship between questionnaire scores and light sensitivity thresholds. RESULTS: = 0.072). UPSIS-17 showed better instrument targeting than KUMC-8 on Rasch analysis. Person-item maps allowed for identification of questions that could be removed without affecting questionnaire validity measures. CONCLUSION:This study resulted in a shortened, 12-item questionnaire. The UPSIS-12 retained significant correlation with both the KUMC-8 and light sensitivity thresholds, yielding a simpler tool for symptom assessment, while retaining validity. This expanded tool may be useful in clinical, as well as research settings, for collection of data about disability due to photophobia.

Elevated intraocular pressure (IOP) is causally implicated in the pathophysiology of primary open-angle glaucoma (POAG). The molecular mechanisms responsible for elevated IOP remain elusive, but may involve aberrant expression and signaling of transforming growth factor (TGF)-β2 within the trabecular meshwork (TM). Consistent with previously published studies, we show here that exogenous addition of TGF-β2 to cultured porcine anterior segments significantly attenuates outflow facility in a time-dependent manner. By comparison, perfusing segments with a TGFβRI/ALK-5 antagonist (SB-431542) unexpectedly elicited a significant and sustained increase in outflow facility, implicating a role for TM-localized constitutive expression and release of TGF-β2. Consistent with this thesis, cultured primary or transformed (GTM3) quiescent human TM cells were found to constitutively express and secrete measurable amounts of biologically-active TGF-β2. Disrupting monomeric GTPase post-translational prenylation and activation with lovastatin or GGTI-298 markedly reduced constitutive TGF-β2 expression and release. Specifically, inhibiting the Rho subfamily of GTPases with C3 exoenzyme similarly reduced constitutive expression and secretion of TGF-β2. These findings suggest that Rho GTPase signaling, in part, regulates constitutive expression and release of biologically-active TGF-β2 from human TM cells. Localized constitutive expression and release of TGF-β2 by TM cells may promote or exacerbate elevation of IOP in POAG.

Primary cilia are required for several signaling pathways, but their function in cellular morphogenesis is poorly understood. Here we show that emergence of an hexagonal cellular pattern during development of the corneal endothelium (CE), a monolayer of neural crest-derived cells that maintains corneal transparency, depends on a precise temporal control of assembly of primary cilia that subsequently disassemble in adult corneal endothelial cells (CECs). However, cilia reassembly occurs rapidly in response to an in vivo mechanical injury and precedes basal body polarization and cellular elongation in mature CECs neighboring the wound. In contrast, CE from hypomorphic IFT88 mutants (Tg737(orpk)) or following in vivo lentiviral-mediated IFT88 knockdown display dysfunctional cilia and show disorganized patterning, mislocalization of junctional markers, and accumulation of cytoplasmic acetylated tubulin. Our results indicate an active role of cilia in orchestrating coordinated morphogenesis of CECs during development and repair and define the murine CE as a powerful in vivo system to study ciliary-based cellular dynamics.