The Krieger Eye Research Laboratory

Petah Tikva, Israel

The Krieger Eye Research Laboratory

Petah Tikva, Israel
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Ehrenberg M.,Rabin Medical Center | Ehrenberg M.,Tel Aviv University | Dratviman-Storobinsky O.,The Krieger Eye Research Laboratory | Avraham-Lubin B.R.,Tel Aviv University | And 3 more authors.
Molecular Vision | Year: 2010

Purpose: Werner syndrome is an autosomal recessive disease of premature aging caused by a polymorphic C1367T mutation in the Werner (WRN) gene. Although there are differences between the pathobiology of normal aging and the phenotype of Werner syndrome, the clinical age-related changes are similar. The aim of the study was to investigate the incidence of the C1367T (rs1346044) polymorphism in patients with age-related cataract. Methods: The study group consisted of 81 patients with senile cataract undergoing cataract extraction surgery. Data on age, sex, and medical history of microvascular disease and cancer were obtained from the medical files. Anterior lens capsule material was collected during surgery. DNA was extracted, amplified by polymerase chain reaction, and screened for the C1367T polymorphism in WRN using restriction enzymes followed by sequencing. Results: There were 33 male and 48 female patients of mean age 74.3±9 years. Genotypic frequencies were 67% for TT and 33% for TC. None of the patients had the CC genotype. Ten patients had a history of myocardial infarct, 8 cerebrovascular accident, and 8 various tumors. The distribution of these morbidities was similar in the two genotype groups. Conclusions: The distribution of the C1367T WRN polymorphism in patients with senile cataract is similar to that in the normal population. Cataract formation in the elderly is not linked to a WRN mutation. © 2010 Molecular Vision.


Avraham-Lubin B.-C.R.,The Krieger Eye Research Laboratory | Avraham-Lubin B.-C.R.,Tel Aviv University | Dratviman-Storobinsky O.,The Krieger Eye Research Laboratory | Dadon-Bar El S.,The Krieger Eye Research Laboratory | And 5 more authors.
Frontiers in Neurology | Year: 2011

The study investigated the therapeutic effect of hyperbaric oxygen (HBO) on anterior ischemic optic neuropathy in a rodent model (rAION). rAION was laser-induced in one eye of 63 mice. The fellow (uninjured) eye served as an internal control.Thirty-three mice under-went two 90-min sessions of 100% oxygen (2 atm) treatment immediately following injury and one session daily thereafter for up to 14 days. The remaining mice were untreated. Retinas were harvested at different time points, and mRNA levels of various genes were analyzed by real-time polymerase chain reaction and histologic study. Untreated mice: day 1 post-rAION - SOD-1 (oxidative-stress-related) decreased to 82% of control (uninjured eye) levels (P< 0.05), Caspase-3 (proapoptotic) decreased to 89%, Bcl-xL mildly increased (117%; all NS); day 3 - HO-1 and endothelial nitric oxide synthase (eNOS; ischaemia-related) decreased to 74%, and Bcl-2-associated X protein, Caspase-3, and B-cell lymphoma 2 (Bcl-2; apoptotic) increased by 170, 120, and 111%, respectively (all NS); day 21 - HO-1 increased to 222% (NS) and eNOS decreased to 48% (P< 0.05).Treated mice: day 1 - SOD-1 and Caspase-3 remained unchanged, Bcl-2 and Bcl-xL mildly increased (112 and 126% respectively); day3-HO-1 and eNOS increased, apoptosis-related gene decreased; day 21 - SOD-1 decreased whereas eNOS increased (P< 0.05), and HO-1 increased to a lesser degree than without treatment. None of the oxygen-treated animals had retinal ganglion cell loss or a decrease inThy-1 expression. In conclusion, HBO treatment after rAION induction influences the expression of apoptosis-related genes as well as oxidative-stress-induced and ischaemia-related genes and may exert a neuroprotective effect. © 2011 Avraham-Lubin, Dratviman-Storobinsky, El, Hasan-reisoglu and Goldenberg-Cohen.


Dratviman-Storobinsky O.,The Krieger Eye Research Laboratory | Cohen Y.,Sheba Cancer Research Center | Frenkel S.,Hebrew University of Jerusalem | Pe'er J.,Hebrew University of Jerusalem | And 3 more authors.
Investigative Ophthalmology and Visual Science | Year: 2010

PURPOSE. Somatic mutations in codon 209 of the GNAQ gene are the first initiating events to be identified in uveal melanoma. The purpose of this study was to search for GNAQ209 mutations in conjunctival melanocytic lesions. METHODS. Forty archival samples of conjunctival melanocytic lesions (conjunctival nevi, primary acquired melanosis, and conjunctival melanoma), 27 samples of uveal melanoma, and 11 samples of uveal melanoma metastases to the liver (3 of which matched primary uveal melanoma samples)-a total of 78 samples from 75 patients- were examined for the presence of GNAQ209 mutations by using chip-based, matrix-assisted laser-desorption time-of-flight (MALDI-TOF) mass spectrometry. Direct sequencing was also performed. RESULTS. The GNAQ209 mutation was identified in 12 (44.5%) uveal melanoma samples and 4 (36.5%) of the 11 metastases of uveal melanoma. It was not detected in any of the other melanocytic lesions. CONCLUSIONS. The GNAQ209 mutation rate in uveal melanoma in this study is in line with the rate in other reports. The finding of the same genotype in the primary tumors and their metastases suggests that mutation in GNAQ is an early event in uveal melanoma tumorigenesis. The lack of GNAQ mutations in conjunctival melanocytic lesions suggests the involvement of a different tumorigenic pathway from that of uveal melanoma. © Association for Research in Vision and Ophthalmology.


Gaydar V.,The Krieger Eye Research Laboratory | Gaydar V.,Bar - Ilan University | Ezrachi D.,Bar - Ilan University | Ezrachi D.,Rabin Medical Center | And 7 more authors.
Investigative Ophthalmology and Visual Science | Year: 2011

Methods. Unilateral central retinal artery occlusion (CRAO) or optic nerve crush (ONC) was induced in 50 mice each, of which 30 were treated with 100% oxygen at 2 atm for 90 minutes immediately after injury and then daily for up to 14 days. Mice were euthanatized on days 1, 3, and 21 for histologic analysis, apoptosis assay, and quantitative real-time polymerase chain reaction test. Findings were analyzed by injury and by treatment. Results. HBO treatment reduced cell loss from 58% to 30% in the CRAO model and from 52% to 32% in the ONC model. In both models, it was associated with significantly increased cell survival in the retinal ganglion cell layer. Expression levels of the proapoptosis genes (bax, caspase-3) decreased minimally in the HBO-treated CRAO mice on day 1, but this trend was reversed on day 3. In the ONC group, levels of caspase-3, bax, and bcl-x increased on day 1 and dropped below baseline on day 3. The pattern of changes in the expression levels of the ischemia- and oxidative-stress-related genes (HO-1, SOD-1, GPX-1, NOX-2) and the effectiveness of HBO treatment varied by model. Overall, however, gene expression levels that increased in the untreated mice increased further with HBO treatment and levels that decreased, decreased further with treatment. Conclusions. HBO treatment protects injured neuronal cells from apoptosis. Response to treatment differs molecularly after ONC or CRAO. These results should prompt clinical trials of acute ischemic retinal damage. © 2011 The Association for Research in Vision and Ophthalmology, Inc.


Morzaev D.,The Krieger Eye Research Laboratory | Morzaev D.,Tel Aviv University | Nicholson J.D.,The Krieger Eye Research Laboratory | Nicholson J.D.,Tel Aviv University | And 8 more authors.
Clinical and Experimental Ophthalmology | Year: 2015

Background: This study aims to investigate the role of the inflammatory response following optic nerve crush (ONC) in knockout mice for the toll-like receptor-4 gene (TLR4-/-) compared to wild-type (WT) mice. Methods: ONC was induced in TLR4-/- and C57BL6 WT mice. Histological sections of the retina and optic nerve were analysed on days 1, 3 or 21 after injury. Molecular analysis with real-time quantitative polymerase chain reaction was used to study the expression of CD45, tumour necrosis-alpha (TNF-α) and glial fibrillary acidic protein, as well as retinal ganglion cell (RGC) markers THY-1 and Brn3b. Results: There was a 25.5% and 38% loss in the RGC layer of the ONC-injured eyes of the TLR4-/- and the WT mice, respectively (with 27% and 9% of the remaining cells positive for Brn3a, respectively). Mean levels of Thy-1 and Brn3b were higher in the TLR4-/- mice. CD45 and Iba1 staining revealed infiltration of inflammatory cells into the injured nerve and retina in both groups. Molecular analysis of the optic nerve on day 1 showed increased TNF-α expression and reduced CD45 and GFAP expression; on day 3, CD45 reverted to baseline but GFAP remained low; on day 21, all 3 markers were at baseline in the TLR4-/- group and decreased in the WT group. Conclusion: Inflammation plays a major role in the response to ONC injury. Reduced levels of inflammation are associated with improved RGC preservation. The increase in TNF-α and reduction in CD45 in both TLR4-/- and WT mice may indicate the presence of an alternative pathway for induction of RGC death. © 2015 Royal Australian and New Zealand College of Ophthalmologists.


Goldenberg-Cohen N.,The Krieger Eye Research Laboratory | Goldenberg-Cohen N.,Tel Aviv University | Avraham-Lubin B.-C.R.,The Krieger Eye Research Laboratory | Avraham-Lubin B.-C.R.,Tel Aviv University | And 3 more authors.
Investigative Ophthalmology and Visual Science | Year: 2014

Purpose. Brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) have limited and transient supportive effects on retinal recovery from ischemia. The aim of this study was to investigate their effect on engrafted adult bone marrow-derived stem cells in a rodent model of anterior ischemic optic neuropathy (rAION). Methods. Small cells were isolated from the bone marrow of green fluorescent protein expressing mice by counterflow centrifugal elutriation, depleted of cells expressing lineage markers, and grafted in conjunction with growth factors into the vitreous body of mice with unilateral rAION. Progenitors were mobilized with granulocyte macrophage colony-stimulating factor (GM-CSF) or stem cell factor (SCF). The contralateral eye served as a control. Results. At 4 weeks, the quantitative incorporation of donor cells in the injured retina was increased by BDNF (P < 0.01 versus control) and decreased by CNTF (P < 0.01 versus control), with no notable difference at 24 weeks. Both growth factors improved the short-term and long-term qualitative engraftment of cells adopting neural phenotypes in the retinal ganglion cell (RGC) layer and astrocyte phenotypes in the anterior vasculature. The RGC-engrafted cells formed extensions toward the inner nuclear layer. In the presence of growth factors, donor cells migrated to the optic nerve and contributed to repair by gliosis. Mobilization with GM-CSF restricted cell fate to microglia, whereas SCF was associated with limited neuroglial differentiation. Conclusions. Both BDNF and CNTF enhance engraftment and neuroglial differentiation of adult bone marrow stem cells in injured retina, with BDNF having an early quantitative and qualitative advantage over CNTF. Mobilization with differentiation factors restricts cell fate in the injured retina. © 2014 The Association for Research in Vision and Ophthalmology, Inc.


PubMed | Tel Aviv University and The Krieger Eye Research Laboratory
Type: Journal Article | Journal: Clinical & experimental ophthalmology | Year: 2015

This study aims to investigate the role of the inflammatory response following optic nerve crush (ONC) in knockout mice for the toll-like receptor-4 gene (TLR4-/-) compared to wild-type (WT) mice.ONC was induced in TLR4-/- and C57BL6 WT mice. Histological sections of the retina and optic nerve were analysed on days 1, 3 or 21 after injury. Molecular analysis with real-time quantitative polymerase chain reaction was used to study the expression of CD45, tumour necrosis-alpha (TNF-) and glial fibrillary acidic protein, as well as retinal ganglion cell (RGC) markers THY-1 and Brn3b.There was a 25.5% and 38% loss in the RGC layer of the ONC-injured eyes of the TLR4-/- and the WT mice, respectively (with 27% and 9% of the remaining cells positive for Brn3a, respectively). Mean levels of Thy-1 and Brn3b were higher in the TLR4-/- mice. CD45 and Iba1 staining revealed infiltration of inflammatory cells into the injured nerve and retina in both groups. Molecular analysis of the optic nerve on day 1 showed increased TNF- expression and reduced CD45 and GFAP expression; on day 3, CD45 reverted to baseline but GFAP remained low; on day 21, all 3 markers were at baseline in the TLR4-/- group and decreased in the WT group.Inflammation plays a major role in the response to ONC injury. Reduced levels of inflammation are associated with improved RGC preservation. The increase in TNF- and reduction in CD45 in both TLR4-/- and WT mice may indicate the presence of an alternative pathway for induction of RGC death.


PubMed | The Krieger Eye Research Laboratory
Type: | Journal: Frontiers in neurology | Year: 2011

The study investigated the therapeutic effect of hyperbaric oxygen (HBO) on anterior ischemic optic neuropathy in a rodent model (rAION). rAION was laser-induced in one eye of 63 mice. The fellow (uninjured) eye served as an internal control. Thirty-three mice underwent two 90-min sessions of 100% oxygen (2atm) treatment immediately following injury and one session daily thereafter for up to 14days. The remaining mice were untreated. Retinas were harvested at different time points, and mRNA levels of various genes were analyzed by real-time polymerase chain reaction and histologic study. Untreated mice: day 1 post-rAION - SOD-1 (oxidative-stress-related) decreased to 82% of control (uninjured eye) levels (P<0.05), Caspase-3 (proapoptotic) decreased to 89%, Bcl-xL mildly increased (117%; all NS); day 3 - HO-1 and endothelial nitric oxide synthase (eNOS; ischaemia-related) decreased to 74%, and Bcl-2-associated X protein, Caspase-3, and B-cell lymphoma 2 (Bcl-2; apoptotic) increased by 170, 120, and 111%, respectively (all NS); day21 - HO-1 increased to 222% (NS) and eNOS decreased to 48% (P<0.05). Treated mice: day 1 - SOD-1 and Caspase-3 remained unchanged, Bcl-2 and Bcl-xL mildly increased (112 and 126% respectively); day 3 - HO-1 and eNOS increased, apoptosis-related gene decreased; day 21 - SOD-1 decreased whereas eNOS increased (P<0.05), and HO-1 increased to a lesser degree than without treatment. None of the oxygen-treated animals had retinal ganglion cell loss or a decrease in Thy-1 expression. In conclusion, HBO treatment after rAION induction influences the expression of apoptosis-related genes as well as oxidative-stress-induced and ischaemia-related genes and may exert a neuroprotective effect.


PubMed | The Krieger Eye Research Laboratory
Type: Journal Article | Journal: Neurobiology of aging | Year: 2012

Mutations in the LMNA gene encoding lamins A/C are responsible for Hutchinson-Gilford syndrome (HGS), a disorder of premature aging. Cataract is 1 of the main manifestations. The most prevalent mutation in Hutchinson-Gilford syndrome is C1824T, which activates a cryptic splice donor site to produce an abnormal lamin A protein. The purpose of this study was to investigate a possible association of the C1824T mutation with age-related cataract. Anterior lens capsule material was collected during cataract extraction surgery from 178 patients with senile cataract during 2007-2008. DNA and mRNA were extracted and sequenced for the LMNA gene. DNA and cDNA were screened for the C1824T mutation, which was not detected. Messenger RNA (mRNA) expression was normal, with no truncation. We found that human age-related nuclear cataract is not associated with LMNA gene mutations or truncation of lamin A.


PubMed | The Krieger Eye Research Laboratory
Type: Comparative Study | Journal: Investigative ophthalmology & visual science | Year: 2014

Brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) have limited and transient supportive effects on retinal recovery from ischemia. The aim of this study was to investigate their effect on engrafted adult bone marrow-derived stem cells in a rodent model of anterior ischemic optic neuropathy (rAION).Small cells were isolated from the bone marrow of green fluorescent protein expressing mice by counterflow centrifugal elutriation, depleted of cells expressing lineage markers, and grafted in conjunction with growth factors into the vitreous body of mice with unilateral rAION. Progenitors were mobilized with granulocyte macrophage colony-stimulating factor (GM-CSF) or stem cell factor (SCF). The contralateral eye served as a control.At 4 weeks, the quantitative incorporation of donor cells in the injured retina was increased by BDNF (P < 0.01 versus control) and decreased by CNTF (P < 0.01 versus control), with no notable difference at 24 weeks. Both growth factors improved the short-term and long-term qualitative engraftment of cells adopting neural phenotypes in the retinal ganglion cell (RGC) layer and astrocyte phenotypes in the anterior vasculature. The RGC-engrafted cells formed extensions toward the inner nuclear layer. In the presence of growth factors, donor cells migrated to the optic nerve and contributed to repair by gliosis. Mobilization with GM-CSF restricted cell fate to microglia, whereas SCF was associated with limited neuroglial differentiation.Both BDNF and CNTF enhance engraftment and neuroglial differentiation of adult bone marrow stem cells in injured retina, with BDNF having an early quantitative and qualitative advantage over CNTF. Mobilization with differentiation factors restricts cell fate in the injured retina.

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