Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence suggests a genetic component to oxygen-induced retinopathy (OIR), a robust experimental model of human retinopathy of prematurity. OIR lends itself well to quantitative analysis of gene expression in rodents with well-defined genetic backgrounds. Such analysis by real-time reverse transcription polymerase chain reaction (RT-PCR) requires the use of reference genes as internal standards for purposes of normalization. We sought to identify housekeeping genes showing stable retinal expression across different rat strains and developmental stages, that were not regulated by oxygen tension. Real-time RT-PCR was used to examine in normal (control) neonatal rat retina the expression of five candidate reference genes: acidic ribosomal phosphoprotein (ARBP), cyclophilin A (CYCA), gamma 2 actin (ACTG2), hypoxanthine guanine phosphoribosyltransferase (HPRT), and RNA polymerase 2 (RNAP2). ACTG2 was poorly expressed, whereas quantification of CYCA was confounded by putative amplification of pseudogenes. Expression of ARBP, HPRT, and RNAP2 was then quantified in dissected retinas from neonatal rats of three inbred strains (Fischer 344, Sprague Dawley, and Dark Agouti) under two different conditions of exposure to inspired oxygen (exposure to room air for 14 days from birth; exposure to cyclic hyperoxia for 14 days from birth). The average variation in relative expression between each pair of these three genes within each of the six cDNA test samples was used to assess stability of gene expression, relative to a standard retinal cDNA pool. The relative expression values for ARBP and HPRT were more closely correlated (r2=0.80) than were those for either gene with RNAP2 (ARBP and RNAP2: r2=0.31; HPRT and RNAP2: r2=0.25). There was little variation among the six experimental groups for the normalized expression of ARBP or HPRT (p>0.05). In contrast, the normalized expression of RNAP2 varied significantly amongst experimental groups: Within each strain, expression was higher in the oxygen-exposed group than in the room air-exposed group (p<0.05). We conclude that ARBP and HPRT exhibit expression that is sufficiently stable under conditions of varying oxygen tension, to permit their use as housekeeping genes in at least one model of OIR in the neonatal rat.
Mol Vis 2007 Aug 29
PMID:Stability of housekeeping gene expression in the rat retina during exposure to cyclic hyperoxia. 1789 50

The expression of intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) were studied in the conjunctiva of diabetic patients with and without retinopathy. All patients underwent a complete ophthalmic examination including ocular fundus and retinal fluorescein angiography. The indirect immunoperoxidase method was performed on 15 normal conjunctivas taken during cataract surgery (group 1), on 40 eyes of 40 patients with type 2 diabetes without diabetic retinopathy (DR) (group 2) and 13 eyes of 13 patients with DR (group 3). ICAM-1 and VCAM-1 are located in epithelial cells, vascular endothelial cells and in stromal cells. Our results show a statistically significant increase in the immunohistochemical expression of these proteins in the conjunctiva of diabetic patients with and without DR in comparison with normal conjunctiva (P = 0.001). Noteworthy, ICAM-1 and VCAM-1 are upregulated in the conjunctiva of diabetic patients with and without retinopathy, reflecting the inflammatory nature of this condition and suggesting a possible role for these mediators in the pathogenesis of diabetic microangiopathy.
J Mol Histol 2008 Apr
PMID:Adhesion molecules (ICAM-1 and VCAM-1) and diabetic retinopathy in type 2 diabetes. 1816 14

Retinal neovascularization is the most common cause of blindness; Retinopathy of pre-maturity (ROP) for children and diabetic retinopathy for young age group. ROP still remains as the most serious cause of vision loss in children. We provided that deguelin significantly reduces retinal neovascularization in a mouse model of ROP. Deguelin never affected the transcriptional activity of hypoxia inducible factor (HIF)-1, however, reduced HIF-1 expression, which led to the decrease of vascular endothelial growth factor expression. Deguelin effectively suppressed endothelial cell proliferation without cytotoxic effect under therapeutic concentration range. In addition, deguelin demonstrated no reduction or retardation in normal retinal development and no retinal toxicity. These data suggest deguelin is a potent inhibitor of retinal neovascularization and may be applied in the treatment of other vasoproliferative retinopathies.
J Cell Mol Med 2008 Dec
PMID:Deguelin inhibits retinal neovascularization by down-regulation of HIF-1alpha in oxygen-induced retinopathy. 1820 62

Regulators of G-protein signaling (RGS) are involved in a wide variety of functions, including olfaction, vision, and cell migration. RGS5 has a perivascular expression pattern and was recently identified as a marker for brain pericytes. This suggests a role for RGS5 in vascular development and pericyte biology. We have created a mouse line which lacks the rgs5 gene and replaced it with a green fluorescent protein (GFP) reporter (rgs5(GFP/GFP)). The mice are viable and fertile and display no obvious developmental defects, and the vasculature appears to develop normally with proper pericyte coverage. Also, no differences were observed in the vasculature under pathological conditions, such as tumor growth and oxygen-induced retinopathy. The GFP expression in pericytes of rgs5(GFP) mice allows detection and sorting of these cells, thereby providing a valuable novel tool for pericyte research.
Mol Cell Biol 2008 Apr
PMID:Generation and characterization of rgs5 mutant mice. 1821 66

Here we report the discovery of and phenotypic characterization of a retinal disorder of unknown origin in adults using clinical, electrophysiological and psychophysical techniques, and to seek the presence of circulating retinal autoantibodies in the sera of these patients. Sixteen patients were identified with progressive bilateral visual loss over a period of months. Ten of the patients were male, and the average age was 55.3 years (range from 43 to 76 years). Known causes such as carcinoma-associated retinopathy, acute zonal occult outer retinopathy and hereditary cone dystrophy appeared unlikely. Investigations included electrophysiology, fundus autofluorescence imaging and psychophysical tests. The sera of these patients were analyzed with indirect immunocytochemistry and Western immunoblot analysis on murine (BALB/c) retinal tissue for the presence of retinal autoantibodies. Bilateral visual loss and photophobia progressed over a period of months to years (average 28.7 months, range 3-67) and subsequently stabilized. No abnormality was observed by biomicroscopy, angiography or autofluorescence imaging. Electrophysiology indicated predominant cone-system dysfunction, either macular or generalized, and post-phototransduction involvement in 9 patients (56%). Photopic and scotopic visual fields and dark adaptation kinetics showed both cone and rod system involvement in all cases. Heterogeneous immunohistochemical staining patterns were seen with the sera of these patients as compared with controls. A majority of the affected patients (9/15) stained with an antinuclear pattern. The retinal autoantibodies from the sera of most patients reacted with the retinal proteins of molecular weight between 34 and 40 kDa. The aetiology of this distinctive retinal disorder therefore appears to be mediated through an autoimmune mechanism.
Exp Mol Pathol 2008 Apr
PMID:Macular and retinal dysfunction of unknown origin in adults with normal fundi: evidence for an autoimmune pathophysiology. 1825 57

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal degeneration. This group of disorders essentially leads to blindness due to mutations in different genes. The genetic basis affected by sporadic and inherited autosomal dominant, autosomal recessive or X-linked mutations is complex. In humans, RP is in most cases associated with missense mutations in the rhodopsin gene (RHO). RHO plays an important role in phototransduction pathways. So far, few studies have described associations between chromosomal alterations and RP. In this study, we present a case report of a premature, 32-week-old male baby who suffered from retinopathy, facial dysmorphisms and other disorders. His chromosomes were analyzed by conventional and high-resolution chromosomal techniques. This analysis revealed structural aberrations on chromosomes 3 and 5 with an apparently balanced chromosomal translocation with karyotype 46,XY,t(3;5)(q25;q11.2). Remarkably, the 3q breakpoint on the long arm of chromosome 3 is located close to the physical RHO chromosomal gene location. In this study, we describe presumably for the first time a possible association between a 3q;5q chromosomal alteration and RP. We conclude that the new detected chromosomal translocation may lead either to loss or inactivation of the intragenic RHO gene or its respective gene regulatory region. As a consequence, the chromosomal aberration may be responsible for retinitis pigmentosa.
Genet Mol Res 2007 Oct 05
PMID:Association between a new 3q;5q chromosomal translocation and dystrophy of human retinal pigment epithelium. 1827 1

Bardet-Biedl syndrome (BBS) is a pleiotropic, genetically heterogeneous disorder characterized by obesity, retinopathy, polydactyly, cognitive impairment, renal and cardiac anomalies, as well as hypertension and diabetes. Multiple genes are known to independently cause BBS. These genes do not appear to code for the same functional category of proteins; yet, mutation of each results in a similar phenotype. Gene knockdown of different BBS genes in zebrafish shows strikingly overlapping phenotypes including defective melanosome transport and disruption of the ciliated Kupffer's vesicle. Here, we demonstrate that individual knockdown of bbs1 and bbs3 results in the same prototypical phenotypes as reported previously for other BBS genes. We utilize the zebrafish system to comprehensively determine whether simultaneous pair-wise knockdown of BBS genes reveals genetic interactions between BBS genes. Using this approach, we demonstrate eight genetic interactions between a subset of BBS genes. The synergistic relationships between distinct combinations are not due to functional redundancy but indicate specific interactions within a multi-subunit BBS complex. In addition, we utilize the zebrafish model system to investigate limb development. Human polydactyly is a cardinal feature of BBS not reproduced in BBS-mouse models. We evaluated zebrafish fin bud patterning and observed altered Sonic hedgehog (shh) expression and subsequent changes to fin skeletal elements. The SHH fin bud phenotype was also used to confirm specific genetic interactions between BBS genes. This study reveals an in vivo requirement for BBS function in limb bud patterning. Our results provide important new insights into the mechanism and biological significance of BBS.
Hum Mol Genet 2008 Jul 01
PMID:Genetic interaction between Bardet-Biedl syndrome genes and implications for limb patterning. 1838 49

Mutations within the inosine 5'-monophosphate dehydrogenase 1 (IMPDH1) gene cause the RP10 form of autosomal dominant retinitis pigmentosa (adRP), an early-onset retinopathy resulting in extensive visual handicap owing to progressive death of photoreceptors. Apart from the prevalence of RP10, estimated to account for 5-10% of cases of adRP in United States and Europe, two observations render this form of RP an attractive target for gene therapy. First, we show that while recombinant adeno-associated viral (AAV)-mediated expression of mutant human IMPDH1 protein in the mouse retina results in an aggressive retinopathy modelling the human counterpart, expression of a normal human IMPDH1 gene under similar conditions has no observable pathological effect on retinal function, indicating that over-expression of a therapeutic replacement gene may be relatively well tolerated. Secondly, complete absence of IMPDH1 protein in mice with a targeted disruption of the gene results in relatively mild retinal dysfunction, suggesting that significant therapeutic benefit may be derived even from the suppression-only component of an RNAi-based gene therapy. We show that AAV-mediated co-expression in the murine retina of a mutant human IMPDH1 gene together with short hairpin RNAs (shRNA) validated in vitro and in vivo, targeting both human and mouse IMPDH1, substantially suppresses the negative pathological effects of mutant IMPDH1, at a point where, in the absence of shRNA, expression of mutant protein in the RP10 model essentially ablates all photoreceptors in transfected areas of the retina. These data strongly suggest that an RNAi-mediated approach to therapy for RP10 holds considerable promise for human subjects.
Hum Mol Genet 2008 Jul 15
PMID:Therapeutic benefit derived from RNAi-mediated ablation of IMPDH1 transcripts in a murine model of autosomal dominant retinitis pigmentosa (RP10). 1838 99

Usher syndrome (USH) is a genetically heterogeneous group of autosomal recessive deaf-blinding disorders. Pathophysiology leading to the blinding retinal degeneration in USH is uncertain. There is evidence for involvement of the photoreceptor cilium, photoreceptor synapse, the adjacent retinal pigment epithelium (RPE) cells, and the Crumbs protein complex, the latter implying developmental abnormalities in the retina. Testing hypotheses has been difficult in murine USH models because most do not show a retinal degeneration phenotype. We defined the retinal disease expression in vivo in human USH using optical imaging of the retina and visual function. In MYO7A (USH1B), results from young individuals or those at early stages indicated the photoreceptor was the first detectable site of disease. Later stages showed photoreceptor and RPE cell pathology. Mosaic retinas in Myo7a-deficient shaker1 mice supported the notion that the mutant photoreceptor phenotype was cell autonomous and not secondary to mutant RPE. Humans with PCDH15 (USH1F), USH2A or GPR98 (USH2C) had a similar retinal phenotype to MYO7A (USH1B). There was no evidence of photoreceptor synaptic dysfunction and no dysplastic phenotype as in CRB1 (Crumbs homologue1) retinopathy. The results point to the photoreceptor cell as the therapeutic target for USH treatment trials, such as MYO7A somatic gene replacement therapy.
Hum Mol Genet 2008 Aug 01
PMID:Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism. 1846 60

Ubiquitous protein kinase CK2 participates in a variety of key cellular functions. We have explored CK2 involvement in angiogenesis. As shown previously, CK2 inhibition reduced endothelial cell proliferation, survival and migration, tube formation, and secondary sprouting on Matrigel. Intraperitoneally administered CK2 inhibitors significantly reduced preretinal neovascularization in a mouse model of proliferative retinopathy. In this model, CK2 inhibitors had an additive effect with somatostatin analog, octreotide, resulting in marked dose reduction for the drug to achieve the same effect. CK2 inhibitors may thus emerge as potent future drugs aimed at inhibiting pathological angiogenesis. Immunostaining of the retina revealed predominant CK2 expression in astrocytes. In human diabetic retinas, mRNA levels of all CK2 subunits decreased, consistent with increased apoptosis. Importantly, a specific CK2 inhibitor prevented recruitment of bone marrow-derived hematopoietic stem cells to areas of retinal neovascularization. This may provide a novel mechanism of action of CK2 inhibitors on newly forming vessels.
Mol Cell Biochem 2008 Sep
PMID:Inhibition of protein kinase CK2 suppresses angiogenesis and hematopoietic stem cell recruitment to retinal neovascularization sites. 1861 2


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