Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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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

Pathological ocular neovascularization, caused by diabetic retinopathy, age-related macular degeneration, or retinopathy of prematurity, is a leading cause of blindness, yet much remains to be learned about its underlying causes. Here we used oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) to assess the contribution of the metalloprotease-disintegrin ADAM9 to ocular neovascularization in mice. Pathological neovascularization in both the OIR and CNV models was significantly reduced in Adam9(-/-) mice compared to wild-type controls. In addition, the level of ADAM9 expression was strongly increased in endothelial cells in pathological vascular tufts in the OIR model. Moreover, tumor growth from heterotopically injected B16F0 melanoma cells was reduced in Adam9(-/-) mice compared to controls. In cell-based assays, the overexpression of ADAM9 enhanced the ectodomain shedding of EphB4, Tie-2, Flk-1, CD40, VCAM, and VE-cadherin, so the enhanced expression of ADAM9 could potentially affect pathological neovascularization by increasing the shedding of these and other membrane proteins from endothelial cells. Finally, we provide the first evidence for the upregulation of ADAM9-dependent shedding by reactive oxygen species, which in turn are known to play a critical role in OIR. Collectively, these results suggest that ADAM9 could be an attractive target for the prevention of proliferative retinopathies, CNV, and cancer.
Mol Cell Biol 2009 May
PMID:ADAM9 is involved in pathological retinal neovascularization. 1927 93

Exposure of preterm infants to hyperoxia impairs vascular growth, contributing to the development of bronchopulmonary dysplasia and retinopathy of prematurity. Disruption of vascular endothelial growth factor (VEGF)-nitric oxide (NO) signaling impairs vascular growth. Endothelial progenitor cells (EPCs) may play an important role in vascular growth. Endothelial colony-forming cells (ECFCs), a type of EPC, from human preterm cord blood are more susceptible to hyperoxia-induced growth impairment than term ECFCs. Therefore, we hypothesized that hyperoxia disrupts VEGF-NO signaling and impairs growth in preterm ECFCs and that exogenous VEGF or NO preserves growth in hyperoxia. Growth kinetics of preterm cord blood-derived ECFCs (gestational ages, 27-34 wk) were assessed in room air (RA) and hyperoxia (40-50% oxygen) with or without VEGF, NO, or N(omega)-nitro-l-arginine. VEGF, VEGF receptor-2 (VEGFR-2), and endothelial NO synthase (eNOS) protein expression and NO production were compared. Compared with RA controls, hyperoxia significantly decreased growth, VEGFR-2 and eNOS expression, and NO production. VEGF treatment restored growth in hyperoxia to values measured in RA controls and significantly increased eNOS expression in hyperoxia. NO treatment also increased growth in hyperoxia. N(omega)-nitro-l-arginine treatment inhibited VEGF-augmented growth in RA and hyperoxia. We conclude that hyperoxia decreases growth and disrupts VEGF-NO signaling in human preterm ECFCs. VEGF treatment restores growth in hyperoxia by increasing NO production. NO treatment also increases growth during hyperoxia. Exogenous VEGF or NO may protect preterm ECFCs from the adverse effects of hyperoxia and preservation of ECFC function may improve outcomes of preterm infants.
Am J Physiol Lung Cell Mol Physiol 2009 Dec
PMID:Hyperoxia disrupts vascular endothelial growth factor-nitric oxide signaling and decreases growth of endothelial colony-forming cells from preterm infants. 1973 18

Single nucleotide polymorphism (SNP) is the simplest form of DNA variation among individuals. These simple changes can be of transition or transversion type and they occur throughout the genome at a frequency of about one in 1,000 bp. They may be responsible for the diversity among individuals, genome evolution, the most common familial traits such as curly hair, interindividual differences in drug response, and complex and common diseases such as diabetes, obesity, hypertension, and psychiatric disorders. SNPs may change the encoded amino acids (nonsynonymous) or can be silent (synonymous) or simply occur in the noncoding regions. They may influence promoter activity (gene expression), messenger RNA (mRNA) conformation (stability), and subcellular localization of mRNAs and/or proteins and hence may produce disease. Therefore, identification of numerous variations in genes and analysis of their effects may lead to a better understanding of their impact on gene function and health of an individual. This improved knowledge may provide a starting point for the development of new, useful SNP markers for medical testing and a safer individualized medication to treat the most common devastating disorders. This will revolutionize the medical field in the future. To illustrate the effect of SNPs on gene function and phenotype, this minireview focuses on evidences revealing the impact of SNPs on the development and progression of three human eye disorders (Norrie disease, familial exudative vitreoretinopathy, and retinopathy of prematurity) that have overlapping clinical manifestations.
Methods Mol Biol 2009
PMID:SNPs: impact on gene function and phenotype. 1976 84

Rho family small GTPases are universal signaling switches in the control of cell polarity in eukaryotic cells. Their polar distribution to the cell cortex is critical for the execution of their functions, yet the mechanism for this distribution is poorly understood. Using a yeast two-hybrid method, we identified RIP1 (ROP interactive partner 1), which belongs to a family of five members of novel proteins that share a C-terminal region that interacts with ROP. When expressed in Arabidopsis pollen, green fluorescence protein GFP-tagged RIP1 was localized to the nucleus of mature pollen. When pollen grains were hydrated in germination medium, GFP-RIP1 switched from the nucleus to the cell cortex at the future pollen germination site and was maintained in the apical cortex of germinating pollen and growing pollen tubes. RIP1 was found to interact with ROP1 in pollen tubes, and the cortical RIP1 localization was influenced by the activity of ROP1. Overexpression of RIP1 induced growth depolarization in pollen tubes, a phenotype similar to that induced by ROP1 overexpression. Interestingly, RIP1 overexpression enhanced GFP-ROP1 recruitment to the plasma membrane (PM) of pollen tubes. Based on these observations, we hypothesize that RIP1 is involved in the positive feedback regulation of ROP1 localization to the PM, leading to the establishment of a polar site for pollen germination and pollen tube growth.
Mol Plant 2008 Nov
PMID:RIP1 (ROP Interactive Partner 1)/ICR1 marks pollen germination sites and may act in the ROP1 pathway in the control of polarized pollen growth. 1982

The leading cause of blindness in the developed world results from several disorders that have pathologic ocular neovascularization as the common pathway leading to vision loss. These disorders include exudative age related macular degeneration (AMD), diabetic retinopathy (DR), retinopathy of prematurity (ROP), retinal vein occlusions (RVO) and ocular tumors. Because neovascularization is the common pathway to blindness in these highly prevalent conditions, the recent understanding of the cascade of angiogenesis has led to clinically available molecular therapeutics that have been proven to restore and preserve vision in patients that suffer from these blinding conditions. This article will summarize the emergence of vascular endothelial growth factor (VEGF) as a validated treatment target for and current understanding of the pathophysiology of ocular neovascularization. The article will then cover promising future strategies and therapeutic targets that are aimed at enhancing the efficacy and/or duration of effect of these clinically available anti-VEGF strategies. In particular molecules that target, VEGF, PDGF, Complement, Inflammation and Integrins that are entering or are currently in clinical trials will be reviewed.
Curr Mol Med 2009 Nov
PMID:Current molecular understanding and future treatment strategies for pathologic ocular neovascularization. 1992 10

Disorders of retinal vascular growth and function are responsible for vision loss in a variety of diseases, including diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity and retinal artery or vein occlusion. Over the past decade, a new signaling pathway that controls retinal vascular development has emerged from the study of inherited disorders - in both humans and mice - that are characterized by retinal hypovascularization. This pathway utilizes a glial-derived extracellular ligand, Norrin, that acts on a transmembrane receptor, Frizzled4, a coreceptor, Lrp5, and an auxiliary membrane protein, Tspan12, on the surface of developing endothelial cells. The resulting signal controls a transcriptional program that regulates endothelial growth and maturation. It will be of great interest to determine whether modulating this pathway could represent a therapeutic approach to human retinal vascular disease.
Trends Mol Med 2010 Sep
PMID:The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease. 2068 66

One of the most frequently observed causes of blindness in infancy is the pathogenesis known as retinopathy of prematurity (ROP). Angiotensin-converting enzyme (ACE) is a vital enzyme in the renin-angiotensin-aldosterone system; it is involved in the development of cardiovascular system diseases linked to I/D polymorphism of the ACE gene. Glutathione-S-transferase enzyme (GST) is one of the most important regulating components of the antioxidant system; there are indications that certain polymorphisms of GST genes (GSTT1, GSTM1), especially the null genotypes, increase the tendency for oxidative stress diseases. We investigated a possible correlation between ACE gene I/D and GSTT1 and GSTM1 gene polymorphisms in 56 prematures suffering from ROP and a control group composed of 48 prematures without ROP in a hospital in Turkey. PCR was used to detect the ACE I/D, GSTT1 and GSTM1 gene polymorphisms. Genotype was determined based on bands formed on agarose gel electrophoresis. We found no significant differences in genotype frequency of the ACE I/D, GSTT1 and GSTM1 genes between normal subjects and patients with ROP. Our results do not support an association of ACE I/D, GSTT1 and GSTM1 gene polymorphisms with risk for ROP.
Genet Mol Res 2010 Oct 26
PMID:Lack of association of genetic polymorphisms of angiotensin-converting enzyme gene I/D and glutathione-S-transferase enzyme T1 and M1 with retinopathy of prematures. 2103 99

Conditions resulting in retinal angiogenesis and edema (exudative age-related macular degeneration, diabetic retinopathy, retinal vein occlusion and retinopathy of prematurity) are major causes of visual impairment, with significant impact on quality of life. There has been increasing clinical usage of anti-vascular endothelial growth factor (anti-VEGF) agents to stop retinal angiogenesis and resolve intraretinal fluid arising from these conditions. However, anti-VEGFs have not been completely successful in curing these conditions, and a range of emerging treatments aimed at supplementing or competing with anti-VEGF agents are being developed. We will discuss the proposed merits these emerging agents bring to the treatment arsenal and how they compare with anti-VEGFs with regards to therapeutic activity, potency, specificity and safety. This review will also highlight recent pre-clinical research findings and suggest where future research might be directed.
J Mol Med (Berl) 2011 Apr
PMID:Emerging therapeutic approaches in the management of retinal angiogenesis and edema. 2117 May 13

AUXIN BINDING PROTEIN 1 (ABP1) has long been proposed as an auxin receptor to regulate cell expansion. The embryo lethality of ABP1-null mutants demonstrates its fundamental role in plant development, but also hinders investigation of its involvement in post-embryonic processes and its mode of action. By taking advantage of weak alleles and inducible systems, several recent studies have revealed a role for ABP1 in organ development, cell polarization, and shape formation. In addition to its role in the regulation of auxin-induced gene expression, ABP1 has now been shown to modulate non-transcriptional auxin responses. ABP1 is required for activating two antagonizing ROP GTPase signaling pathways involved in cytoskeletal reorganization and cell shape formation, and participates in the regulation of clathrin-mediated endocytosis to subsequently affect PIN protein distribution. These exciting discoveries provide indisputable evidence for the auxin-induced signaling pathways that are downstream of ABP1 function, and suggest intriguing mechanisms for ABP1-mediated polar cell expansion and spatial coordination in response to auxin.
Mol Plant 2011 Jul
PMID:Is ABP1 an auxin receptor yet? 2171 49


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