Person: Ksander, Bruce
Loading...
Email Address
AA Acceptance Date
Birth Date
Research Projects
Organizational Units
Job Title
Last Name
Ksander
First Name
Bruce
Name
Ksander, Bruce
9 results
Search Results
Now showing 1 - 9 of 9
Publication Soluble Guanylate Cyclase a1–Deficient Mice: a novel murine model for Primary Open Angle Glaucoma(Indian Academy of Neurosciences, 2013) Buys, Emmanuel; Ko, Yu-Chieh; Alt, Clemens; Hayton, Sarah R.; Jones, Alexander; Tainsh, Laurel T.; Ren, Ruiyi; Giani, Andrea; Clerte’, Maeva; Abernathy, Emma; Tainsh, Robert E. T.; Oh, Dong-Jin; Malhotra, Rajeev; Arora, Pankaj; de Waard, Nadine; Yu, Binglan; Turcotte, Raphael; Nathan, Daniel; Scherrer-Crosbie, Marielle; Loomis, Stephanie J.; Kang, Jae Hee; Lin, Charles; Gong, Haiyan; Rhee, Douglas J.; Brouckaert, Peter; Wiggs, Janey; Gregory-Ksander, Meredith; Pasquale, Louis; Bloch, Kenneth D.; Ksander, BrucePublication Regulation of intraocular pressure by soluble and membrane guanylate cyclases and their role in glaucoma(Frontiers Media S.A., 2014) Buys, Emmanuel; Potter, Lincoln R.; Pasquale, Louis; Ksander, BruceGlaucoma is a progressive optic neuropathy characterized by visual field defects that ultimately lead to irreversible blindness (Alward, 2000; Anderson et al., 2006). By the year 2020, an estimated 80 million people will have glaucoma, 11 million of which will be bilaterally blind. Primary open-angle glaucoma (POAG) is the most common type of glaucoma. Elevated intraocular pressure (IOP) is currently the only risk factor amenable to treatment. How IOP is regulated and can be modulated remains a topic of active investigation. Available therapies, mostly geared toward lowering IOP, offer incomplete protection, and POAG often goes undetected until irreparable damage has been done, highlighting the need for novel therapeutic approaches, drug targets, and biomarkers (Heijl et al., 2002; Quigley, 2011). In this review, the role of soluble (nitric oxide (NO)-activated) and membrane-bound, natriuretic peptide (NP)-activated guanylate cyclases that generate the secondary signaling molecule cyclic guanosine monophosphate (cGMP) in the regulation of IOP and in the pathophysiology of POAG will be discussed.Publication NLRP3 Inflammasome Activation in Retinal Pigment Epithelial Cells by Lysosomal Destabilization: Implications for Age-Related Macular Degeneration(Association for Research in Vision and Ophthalmology (ARVO), 2013) Tseng, Wenche; Thein, Thuzar; Kinnunen, Kati; Lashkari, Kameran; Gregory, Meredith S.; D'Amore, Patricia; Ksander, BrucePurpose.: To evaluate the effect of lysosomal destabilization on NLRP3 inflammasome activation in RPE cells and to investigate the mechanisms by which inflammasome activation may contribute to the pathogenesis of age-related macular degeneration (AMD). Methods.: Human ocular tissue sections from patients with geographic atrophy or neovascular AMD were stained for NLRP3 and compared to tissues from age-matched controls. Expression of the IL-1β precursor, pro-IL-1β, was induced in ARPE-19 cells by IL-1α treatment. Immunoblotting was performed to assess expression of NLRP3 inflammasome components (NLRP3, ASC, and procaspase-1) and pro-IL-1β in ARPE-19 cells. Lysosomes were destabilized using the lysosomotropic agent L-leucyl-L-leucine methyl ester (Leu-Leu-OMe). Active caspase-1 was detected using FAM-YVAD-FMK, a fluorescent-labeled inhibitor of caspases (FLICA) specific for caspase-1. IL-1β was detected by immunoblotting and ELISA, and cytotoxicity was evaluated by LDH quantification. Results.: RPE of eyes affected by geographic atrophy or neovascular AMD exhibited NLRP3 staining at lesion sites. ARPE-19 cells were found to express NLRP3, ASC, and procaspase-1. IL-1α dose-dependently induced pro-IL-1β expression in ARPE-19 cells. Lysosomal destabilization induced by Leu-Leu-OMe triggered caspase-1 activation, IL-1β secretion, and ARPE-19 cell death. Blocking Leu-Leu-OMe–induced lysosomal disruption with the compound Gly-Phe-CHN2 or inhibiting caspase-1 with Z-YVAD-FMK abrogated IL-1β release and ARPE-19 cytotoxicity. Conclusions.: NLRP3 upregulation occurs in the RPE during the pathogenesis of advanced AMD, in both geographic atrophy and neovascular AMD. Destabilization of RPE lysosomes induces NLRP3 inflammasome activation, which may contribute to AMD pathology through the release of the proinflammatory cytokine IL-1β and through caspase-1-mediated cell death, known as “pyroptosis.”Publication B-Crystallin Protects Retinal Tissue during Staphylococcus aureus- Induced Endophthalmitis(American Society for Microbiology, 2008) Whiston, E. A.; Sugi, N.; Kamradt, M. C.; Sack, C.; Heimer, S. R.; Engelbert, M.; Wawrousek, E. F.; Gilmore, Michael; Ksander, Bruce; Gregory, M. S.Bacterial infections of the eye highlight a dilemma that is central to all immune-privileged sites. On the one hand, immune privilege limits inflammation to prevent bystander destruction of normal tissue and loss of vision. On the other hand, bacterial infections require a robust inflammatory response for rapid clearance of the pathogen. We demonstrate that the retina handles this dilemma, in part, by activation of a protective heat shock protein. During Staphylococcus aureus-induced endophthalmitis, the small heat shock protein αB-crystallin is upregulated in the retina and prevents apoptosis during immune clearance of the bacteria. In the absence of αB-crystallin, mice display increased retinal apoptosis and retinal damage. We found that S. aureus produces a protease capable of cleaving αB-crystallin to a form that coincides with increased retinal apoptosis and tissue destruction. We conclude that αB-crystallin is important in protecting sensitive retinal tissue during destructive inflammation that occurs during bacterial endophthalmitis.Publication Spontaneous Bacterial Keratitis in CD36 Knockout Mice(Association for Research in Vision and Ophthalmology (ARVO), 2011) Klocke, Julia; Barcia, Rita N.; Heimer, Susan; Cario, Elke; Zieske, James; Gilmore, Michael; Ksander, Bruce; Gregory-Ksander, MeredithPurpose: CD36 is a Class B scavenger receptor that is constitutively expressed in the corneal epithelium and has been implicated in many homeostatic functions, including the homeostasis of the epidermal barrier. The aim of this study is to determine (1) whether CD36 is required for the maintenance of the corneal epithelial barrier to infection, and (2) whether CD36-deficient mice present with an increased susceptibility to bacterial keratitis. Methods: The corneas of CD36−/−, TSP1−/−, TLR2−/−, and C57BL/6 WT mice were screened via slit lamp microscopy or ex vivo analysis. The epithelial tight junctions and mucin layer were assessed via LC-biotin and Rose Bengal staining, respectively. Bacterial quantification was performed on corneal buttons and GFP-expressing Staphylococcus aureus was used to study bacterial binding. Results: CD36−/− mice develop spontaneous corneal defects that increased in frequency and severity with age. The mild corneal defects were characterized by a disruption in epithelial tight junctions and the mucin layer, an infiltrate of macrophages, and increased bacterial binding. Bacterial quantification revealed high levels of Staphylococcus xylosus in the corneas of CD36−/− mice with severe defects, but not in wild-type controls. Conclusions: CD36−/− mice develop spontaneous bacterial keratitis independent of TLR2 and TSP1. The authors conclude that CD36 is a critical component of the corneal epithelial barrier, and in the absence of CD36 the barrier breaks down, allowing bacteria to bind to the corneal epithelium and resulting in spontaneous keratitis. This is the first report of spontaneous bacterial keratitis in mice.Publication Endomucin prevents leukocyte–endothelial cell adhesion and has a critical role under resting and inflammatory conditions(Nature Publishing Group, 2016) Zahr, Alisar; Alcaide, Pilar; Yang, Jinling; Jones, Alexander; Gregory, Meredith; dela Paz, Nathaniel G.; Patel-Hett, Sunita; Nevers, Tania; Koirala, Adarsha; Luscinskas, Francis; Saint-Geniez, Magali; Ksander, Bruce; D'Amore, Patricia; Argueso, PabloEndomucin is a membrane-bound glycoprotein expressed luminally by endothelial cells that line postcapillary venules, a primary site of leukocyte recruitment during inflammation. Here we show that endomucin abrogation on quiescent endothelial cells enables neutrophils to adhere firmly, via LFA-1-mediated binding to ICAM-1 constitutively expressed by endothelial cells. Moreover, TNF-α stimulation downregulates cell surface expression of endomucin concurrent with increased expression of adhesion molecules. Adenovirus-mediated expression of endomucin under inflammatory conditions prevents neutrophil adhesion in vitro and reduces the infiltration of CD45+ and NIMP-R14+ cells in vivo. These results indicate that endomucin prevents leukocyte contact with adhesion molecules in non-inflamed tissues and that downregulation of endomucin is critical to facilitate adhesion of leukocytes into inflamed tissues.Publication Local Treatment With Alpha-Melanocyte Stimulating Hormone Reduces Corneal Allorejection(Ovid Technologies (Wolters Kluwer Health), 2009) Hamrah, Pedram; Haskova, Zdenka; Taylor, Andrew W.; Zhang, Qiang; Ksander, Bruce; Dana, RezaBackground Corneal grafting is by far the most common form of transplantation. Many grafts suffer from immune rejection and current therapies are associated with many side effects, requiring more effective and safe therapies. Alpha–melanocyte stimulating hormone (α–MSH) is a neuropeptide that suppresses host inflammatory defense mechanisms. The purpose of this study was to determine the role of local therapy with α-MSH on corneal allograft survival, and the mechanisms by which it may influence graft outcome. Methods Orthotopic corneal transplantation was performed, with recipients receiving subconjunctival α-MSH or sham injections twice weekly. Grafts were followed for 70 days and graft inflammation/opacification was compared between the two groups in a masked fashion. Graft infiltration and ocular gene expression of select inflammatory cytokines was evaluated at different timepoints. Additionally, allospecific delayed type hypersensitivity (DTH) was compared among the groups 3 weeks post transplantation. Results Results showed a significant increase in corneal graft survival in α-MSH-treated recipients as compared to controls. While 75% of allografts in α-MSH-treated hosts survived at 70 days, 43% survived in controls (p=0.04). Graft infiltration studies demonstrated a significant decrease in the number of mononuclear and polymorphonuclear cells in α-MSH-treated mice as compared to controls at days 7 and 14 after transplantation. Further, allospecific DTH and gene expression of interferon-γ and interleukin-2 showed a significantly reduced expression in α-MSH-treated mice as compared to controls. Conclusions In this study, we provide for the first time, in vivo evidence that treatment with local α-MSH may significantly reduce allorejection of orthotopic transplants.Publication Soluble Guanylate Cyclase α1–Deficient Mice: A Novel Murine Model for Primary Open Angle Glaucoma(Public Library of Science, 2013) Ko, Yu-Chieh; Hayton, Sarah R.; Jones, Alexander; Tainsh, Laurel T.; Ren, Ruiyi; Giani, Andrea; Clerté, Maeva; Abernathy, Emma; de Waard, Nadine; Turcotte, Raphael; Nathan, Daniel; Loomis, Stephanie J.; Gong, Haiyan; Brouckaert, Peter; Buys, Emmanuel; Alt, Clemens; Tainsh, Robert; Oh, Dong-Jin; Malhotra, Rajeev; Arora, Pankaj; Yu, Binglan; Scherrer-Crosbie, Marielle; Kang, Jae Hee; Lin, Charles; Rhee, Douglas J; Wiggs, Janey; Gregory-Ksander, Meredith; Pasquale, Louis; Bloch, Kenneth; Ksander, BrucePrimary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the \(α_1\) subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase \(α_1\)–deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the \(α_1\) and \(β_1\) subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG.Publication Opposing Roles For Membrane Bound and Soluble Fas Ligand in Glaucoma-Associated Retinal Ganglion Cell Death(Public Library of Science, 2011) Hackett, Caroline G.; Abernathy, Emma F.; Hohlbaum, Andreas M.; Moody, Krishna-sulayman L.; Hobson, Maura W.; Jones, Alexander; Karray, Saoussen; Giani, Andrea; John, Simon W. M.; Marshak-Rothstein, Ann; Gregory-Ksander, Meredith; Lee, Karen S.; Saff, Rebecca; Kolovou, Paraskevi-Evi; Chen, Dong; Ksander, BruceGlaucoma, the most frequent optic neuropathy, is a leading cause of blindness worldwide. Death of retinal ganglion cells (RGCs) occurs in all forms of glaucoma and accounts for the loss of vision, however the molecular mechanisms that cause RGC loss remain unclear. The pro-apoptotic molecule, Fas ligand, is a transmembrane protein that can be cleaved from the cell surface by metalloproteinases to release a soluble protein with antagonistic activity. Previous studies documented that constitutive ocular expression of FasL maintained immune privilege and prevented neoangeogenesis. We now show that FasL also plays a major role in retinal neurotoxicity. Importantly, in both TNF \(\alpha\) triggered RGC death and a spontaneous model of glaucoma, gene-targeted mice that express only full-length FasL exhibit accelerated RGC death. By contrast, FasL-deficiency, or administration of soluble FasL, protected RGCs from cell death. These data identify membrane-bound FasL as a critical effector molecule and potential therapeutic target in glaucoma.