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Search Results: 1 - 10 of 144764 matches for " Neena B Haider "
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Patterned Neuroprotection in the Inpp4awbl Mutant Mouse Cerebellum Correlates with the Expression of Eaat4
Andrew J. Sachs,Samuel A. David,Neena B. Haider,Arne M. Nystuen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008270
Abstract: The weeble mutant mouse has a frame shift mutation in inositol polyphosphate 4-phosphatase type I (Inpp4a). The phenotype is characterized by an early onset cerebellar ataxia and neurodegeneration, especially apparent in the Purkinje cells. Purkinje cell loss is a common pathological finding in many human and mouse ataxic disorders. Here we show that in the Inpp4awbl mutant, Purkinje cells are lost in a specific temporal and spatial pattern. Loss occurs early in postnatal development; however, prior to the appearance of climbing fibers in the developing molecular layer, the mutant has a normal complement of Purkinje cells and they are properly positioned. Degeneration and reactive gliosis are present at postnatal day 5 and progress rapidly in a defined pattern of patches; however, Inpp4a is expressed uniformly across Purkinje cells. In late stage mutants, patches of surviving Purkinje cells appear remarkably normal with the exception that the climbing fibers have been excessively eliminated. Surviving Purkinje cells express Eaat4, a glutamate transporter that is differentially expressed in subsets of Purkinje cells during development and into adult stages. Prior to Purkinje cell loss, reactive gliosis and dendritic atrophy can be seen in Eaat4 negative stripes. Our data suggest that Purkinje cell loss in the Inpp4awbl mutant is due to glutamate excitotoxicity initiated by the climbing fiber, and that Eaat4 may exert a protective effect.
Modifier Genes as Therapeutics: The Nuclear Hormone Receptor Rev Erb Alpha (Nr1d1) Rescues Nr2e3 Associated Retinal Disease
Nelly M. Cruz, Yang Yuan, Barrett D. Leehy, Rinku Baid, Uday Kompella, Margaret M. DeAngelis, Pascal Escher, Neena B. Haider
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0087942
Abstract: Nuclear hormone receptors play a major role in many important biological processes. Most nuclear hormone receptors are ubiquitously expressed and regulate processes such as metabolism, circadian function, and development. They function in these processes to maintain homeostasis through modulation of transcriptional gene networks. In this study we evaluate the effectiveness of a nuclear hormone receptor gene to modulate retinal degeneration and restore the integrity of the retina. Currently, there are no effective treatment options for retinal degenerative diseases leading to progressive and irreversible blindness. In this study we demonstrate that the nuclear hormone receptor gene Nr1d1 (Rev-Erbα) rescues Nr2e3-associated retinal degeneration in the rd7 mouse, which lacks a functional Nr2e3 gene. Mutations in human NR2E3 are associated with several retinal degenerations including enhanced S cone syndrome and retinitis pigmentosa. The rd7 mouse, lacking Nr2e3, exhibits an increase in S cones and slow, progressive retinal degeneration. A traditional genetic mapping approach previously identified candidate modifier loci. Here, we demonstrate that in vivo delivery of the candidate modifier gene, Nr1d1 rescues Nr2e3 associated retinal degeneration. We observed clinical, histological, functional, and molecular restoration of the rd7 retina. Furthermore, we demonstrate that the mechanism of rescue at the molecular and functional level is through the re-regulation of key genes within the Nr2e3-directed transcriptional network. Together, these findings reveal the potency of nuclear receptors as modulators of disease and specifically of NR1D1 as a novel therapeutic for retinal degenerations.
Nuclear Receptor Rev-erb Alpha (Nr1d1) Functions in Concert with Nr2e3 to Regulate Transcriptional Networks in the Retina
Nissa J. Mollema,Yang Yuan,Austin S. Jelcick,Andrew J. Sachs,Désirée von Alpen,Daniel Schorderet,Pascal Escher,Neena B. Haider
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017494
Abstract: The majority of diseases in the retina are caused by genetic mutations affecting the development and function of photoreceptor cells. The transcriptional networks directing these processes are regulated by genes such as nuclear hormone receptors. The nuclear hormone receptor gene Rev-erb alpha/Nr1d1 has been widely studied for its role in the circadian cycle and cell metabolism, however its role in the retina is unknown. In order to understand the role of Rev-erb alpha/Nr1d1 in the retina, we evaluated the effects of loss of Nr1d1 to the developing retina and its co-regulation with the photoreceptor-specific nuclear receptor gene Nr2e3 in the developing and mature retina. Knock-down of Nr1d1 expression in the developing retina results in pan-retinal spotting and reduced retinal function by electroretinogram. Our studies show that NR1D1 protein is co-expressed with NR2E3 in the outer neuroblastic layer of the developing mouse retina. In the adult retina, NR1D1 is expressed in the ganglion cell layer and is co-expressed with NR2E3 in the outer nuclear layer, within rods and cones. Several genes co-targeted by NR2E3 and NR1D1 were identified that include: Nr2c1, Recoverin, Rgr, Rarres2, Pde8a, and Nupr1. We examined the cyclic expression of Nr1d1 and Nr2e3 over a twenty-four hour period and observed that both nuclear receptors cycle in a similar manner. Taken together, these studies reveal a novel role for Nr1d1, in conjunction with its cofactor Nr2e3, in regulating transcriptional networks critical for photoreceptor development and function.
Genetic Variations Strongly Influence Phenotypic Outcome in the Mouse Retina
Austin S. Jelcick, Yang Yuan, Barrett D. Leehy, Lakeisha C. Cox, Alexandra C. Silveira, Fang Qiu, Sarah Schenk, Andrew J. Sachs, Margaux A. Morrison, Arne M. Nystuen, Margaret M. DeAngelis, Neena B. Haider
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021858
Abstract: Variation in genetic background can significantly influence the phenotypic outcome of both disease and non-disease associated traits. Additionally, differences in temporal and strain specific gene expression can also contribute to phenotypes in the mammalian retina. This is the first report of microarray based cross-strain analysis of gene expression in the retina investigating genetic background effects. Microarray analyses were performed on retinas from the following mouse strains: C57BL6/J, AKR/J, CAST/EiJ, and NOD.NON-H2-nb1 at embryonic day 18.5 (E18.5) and postnatal day 30.5 (P30.5). Over 3000 differentially expressed genes were identified between strains and developmental stages. Differential gene expression was confirmed by qRT-PCR, Western blot, and immunohistochemistry. Three major gene networks were identified that function to regulate retinal or photoreceptor development, visual perception, cellular transport, and signal transduction. Many of the genes in these networks are implicated in retinal diseases such as bradyopsia, night-blindness, and cone-rod dystrophy. Our analysis revealed strain specific variations in cone photoreceptor cell patterning and retinal function. This study highlights the substantial impact of genetic background on both development and function of the retina and the level of gene expression differences tolerated for normal retinal function. These strain specific genetic variations may also be present in other tissues. In addition, this study will provide valuable insight for the development of more accurate models for human retinal diseases.
Influence of ROBO1 and RORA on Risk of Age-Related Macular Degeneration Reveals Genetically Distinct Phenotypes in Disease Pathophysiology
Gyungah Jun, Michael Nicolaou, Margaux A. Morrison, Jacqueline Buros, Denise J. Morgan, Monte J. Radeke, Yoshihiro Yonekawa, Evangelia E. Tsironi, Maria G. Kotoula, Fani Zacharaki, Nissa Mollema, Yang Yuan, Joan W. Miller, Neena B. Haider, Gregory S. Hageman, Ivana K. Kim, Debra A. Schaumberg, Lindsay A. Farrer, Margaret M. DeAngelis
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025775
Abstract: ROBO1 is a strong candidate gene for age-related macular degeneration (AMD) based upon its location under a linkage peak on chromosome 3p12, its expression pattern, and its purported function in a pathway that includes RORA, a gene previously associated with risk for neovascular AMD. Previously, we observed that expression of ROBO1 and RORA is down-regulated among wet AMD cases, as compared to their unaffected siblings. Thus, we hypothesized that contribution of association signals in ROBO1, and interaction between these two genes may be important for both wet and dry AMD. We evaluated association of 19 single nucleotide polymorphisms (SNPs) in ROBO1 with wet and dry stages of AMD in a sibling cohort and a Greek case-control cohort containing 491 wet AMD cases, 174 dry AMD cases and 411 controls. Association signals and interaction results were replicated in an independent prospective cohort (1070 controls, 164 wet AMD cases, 293 dry AMD cases). The most significantly associated ROBO1 SNPs were rs1387665 under an additive model (meta P = 0.028) for wet AMD and rs9309833 under a recessive model (meta P = 6×10?4) for dry AMD. Further analyses revealed interaction between ROBO1 rs9309833 and RORA rs8034864 for both wet and dry AMD (interaction P<0.05). These studies were further supported by whole transcriptome expression profile studies from 66 human donor eyes and chromatin immunoprecipitation assays from mouse retinas. These findings suggest that distinct ROBO1 variants may influence the risk of wet and dry AMD, and the effects of ROBO1 on AMD risk may be modulated by RORA variants.
Orally Active Multi-Functional Antioxidants Are Neuroprotective in a Rat Model of Light-Induced Retinal Damage
James Randazzo, Zifeng Zhang, Michael Hoff, Hiroyoshi Kawada, Andrew Sachs, Yang Yuan, Neena Haider, Peter Kador
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021926
Abstract: Background Progression of age-related macular degeneration has been linked to iron dysregulation and oxidative stress that induce apoptosis of neural retinal cells. Since both antioxidants and chelating agents have been reported to reduce the progression of retinal lesions associated with AMD in experimental animals, the present study evaluates the ability of multi-functional antioxidants containing functional groups that can independently chelate redox metals and quench free radicals to protect the retina against light-induced retinal degeneration, a rat model of dry atrophic AMD. Methods/Results Proof of concept studies were conducted to evaluate the ability of 4-(5-hydroxypyrimidin-2-yl)-N,N-dimethyl?-3,5-dioxopiperazine-1-sulfonamide(compound 4) and 4-(5-hydroxy-4,6-dimethoxypyrimidin-2-yl?)-N,N-dimethyl-3,5-dioxopiperazine-1-sul?fonamide(compound 8) to reduce retinal damage in 2-week dark adapted Wistar rats exposed to 1000 lx of light for 3 hours. Assessment of the oxidative stress markers 4- hydroxynonenal and nitrotyrosine modified proteins and Thioredoxin by ELISA and Western blots indicated that these compounds reduced the oxidative insult caused by light exposure. The beneficial antioxidant effects of these compounds in providing significant functional and structural protection were confirmed by electroretinography and quantitative histology of the retina. Conclusions/Significance The present study suggests that multi-functional compounds may be effective candidates for preventive therapy of AMD.
Systems biology-based analysis implicates a novel role for vitamin D metabolism in the pathogenesis of age-related macular degeneration
Margaux A Morrison, Alexandra C Silveira, Nancy Huynh, Gyungah Jun, Silvia E Smith, Fani Zacharaki, Hajime Sato, Stephanie Loomis, Michael T Andreoli, Scott M Adams, Monte J Radeke, Austin S Jelcick, Yang Yuan, Aristoteles N Tsiloulis, Dimitrios Z Chatzoulis, Giuliana Silvestri, Maria G Kotoula, Evangelia E Tsironi, Bruce W Hollis, Rui Chen, Neena B Haider, Joan W Miller, Lindsay A Farrer, Gregory S Hageman, Ivana K Kim, Debra A Schaumberg, Margaret M DeAngelis
Human Genomics , 2011, DOI: 10.1186/1479-7364-5-6-538
Abstract: Based on the relationship between ultraviolet irradiance and vitamin D production, we employed a candidate gene approach for evaluating common variation in key vitamin D pathway genes (the genes encoding the vitamin D receptor [VDR]; cytochrome P450, family 27, subfamily B, polypeptide 1 [CYP27B1]; cytochrome P450, family 24, subfamily A, polypeptide 1 [CYP24A1]; and CYP27A1) in this same family-based cohort. Initial findings were then validated and replicated in the extended family cohort, an unrelated case-control cohort from central Greece and a prospective nested case-control population from the Nurse's Health Study and Health Professionals Follow-Up Studies, which included patients with all subtypes of AMD for a total of 2,528 individuals. Single point variants in CYP24A1 (the gene encoding the catabolising enzyme of the vitamin D pathway) were demonstrated to influence AMD risk after controlling for smoking history, sex and age in all populations, both separately and, more importantly, in a meta-analysis. This is the first report demonstrating a genetic association between vitamin D metabolism and AMD risk. These findings were also supplemented with expression data from human donor eyes and human retinal cell lines. These data not only extend previous biological studies in the AMD field, but further emphasise common antecedents between several disorders with an inflammatory/immunogenic component such as cardiovascular disease, cancer and AMD.Several biological processes/cellular pathways involved in conditions such as cancer, cardiovascular disease and type 1 diabetes have also been implicated in the pathophysiology of the neovascular form of age-related macular degeneration (AMD). AMD, a disease characterised by the loss of ability to drive, recognise faces and read, is the leading cause of blindness in the US elderly population. Most prominent among these shared disease-associated processes is angiogenesis, the defining hallmark of neovascular AMD [1-3]. Add
Novel Diabetic Mouse Models as Tools for Investigating Diabetic Retinopathy
Peter F. Kador, Peng Zhang, Jun Makita, Zifeng Zhang, Changmei Guo, James Randazzo, Hiroyoshi Kawada, Neena Haider, Karen Blessing
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049422
Abstract: Objective Mouse models possessing green fluorescent protein (GFP) and/or human aldose reductase (hAR) in vascular tissues have been established and crossed with naturally diabetic Akita mice to produce new diabetic mouse models. Research Design and Methods Colonies of transgenic C57BL mice expressing GFP (SMAA-GFP), hAR (SMAA-hAR) or both (SMAA-GFP-hAR) in vascular tissues expressing smooth muscle actin were established and crossbred with C57BL/6-Ins2Akita/J (AK) mice to produce naturally diabetic offspring AK-SMAA-GFP and AK-SMAA-GFP-hAR. Aldose reductase inhibitor AL1576 (ARI) was administered in chow. Retinal and lenticular sorbitol levels were determined by HPLC. Retinal functions were evaluated by electroretinography (ERGs). Growth factor and signaling changes were determined by Western Blots using commercially available antibodies. Retinal vasculatures were isolated from the neural retina by enzymatic digestion. Flat mounts were stained with PAS-hematoxylin and analyzed. Results Akita transgenics developed DM by 8 weeks of age with blood glucose levels higher in males than females. Sorbitol levels were higher in neural retinas of AK-SMAA-GFP-hAR compared to AK-SMAA-GFP mice. AK-SMAA-GFP-hAR mice also had higher VEGF levels and reduced ERG scotopic b-wave function, both of which were normalized by AL1576. AK-SMAA-GFP-hAR mice showed induction of the retinal growth factors bFGF, IGF-1, and TGFβ, as well as signaling changes in P-Akt, P-SAPK/JNK and P-44/42 MAPK that were also reduced by ARI treatment. Quantitative analysis of flat mounts in 18 week AK-SMAA-GFP-hAR mice revealed increased loss of nuclei/capillary length and a significant increase in the percentage of acellular capillaries present which was not seen in AK-SMAA-GFP-hAR treated with ARI. Conclusions/Significance These new mouse models of early onset diabetes may be valuable tools for assessing both the role of hyperglycemia and AR in the development of retinal lesions associated with diabetic retinopathy.
Association of β2-adrenergic receptor and insulin receptor substrate-1 polymorphisms with obesity in a Northern Indian population
Srivastava Neena,Achyut B,Prakash Jai,Agarwal C
Indian Journal of Human Genetics , 2008,
Abstract: Background: Imbalance in hormonal levels, regulated by host genetic factors, are known to be a major cause of obesity. Therefore, we aimed to evaluate association of genetic polymorphisms of β2 -adrenergic receptor (β2 -AR) and insulin receptor substrate-1 (IRS-1) with hormonal levels in northern Indian obese. Methods: A total of 111 obese and 89 age matched non-obese subjects were studied after taking detailed clinical profile. Hormonal assays in serum/plasma for different hormones were done using IRMA and RIA kits. Genetic analysis of β2 -AR (-47 and -20, T to C) and IRS-1 (Arg972Gly) was done using PCR-RFLP. Statistical Analysis: Statistical analysis was performed by SPSS (version 11.5) software. All continuous variables were expressed as mean ± SD and tested by ANOVA test. Comparisons of categorical variables were assessed using X2 tests or Fisher′s exact test. P-value < 0.05 was considered as significant. Results: Analysis showed that obese subjects had significantly higher value of blood pressure (systolic), WHR, leptin insulin and glucagon and lower value of GH. In β2 -AR (-47) T/C and IRS-1 Gly972Arg gene polymorphisms we did not found significant differences in genotype or allele frequencies. Moreover, none of the studied hormonal or metabolic parameters showed any association with the gene polymorphisms. Conclusions: Study reveals no significant association of β2 -AR (-47 and -20, T to C) and IRS-1 Gly 972 Arg polymorphisms with obesity in northern Indians.
A technique for obtaining monokaryotic haploid hyphae of Ustilago tritici, causal agent of wheat loose smut
B. SHARIFNABI, NEENA MITTER and A.K. SARBHOY
Indian Phytopathology , 2012,
Abstract: Twenty isolates of Ustilago tritici [U. segetum var. tritici] were collected from various parts of northern India and used for monokaryotic haplont production. Teliospores from the infected wheat samples were surface sterilized and 150-250 mul of sterilized teliospore suspension was evenly spread on Petri dishes containing 1.5-2 mm thick, 1.5% water agar and DL-aspartic acid (0.147 mg/ml water). The Petri dishes were incubated at 20℃ for about 30 hours. Dikaryon formation was observed and subsequently 1 cm2 blocks of medium from these plates were transferred to plates of 1/5 normal nutrient concentration of potato dextrose agar and incubated in the refrigerator overnight. The squares were then transferred to another layer of 1/5 PDA pre-warmed to25?and kept at this temperature for 4-6 hours. Monokaryotic haploid hyphae were obtained and isolated by microsurgery with very thin Pasteur pipettes and transferred to a thick layer of 1/5 PDA and kept at 20? Growth of haplonts was relatively slow and was visible only after 4-5 days. After 2 weeks, the verrucose colonies of fungus which were dense, cream to pinkish cream, could be seen. The mycelial mass production of the mycelium of haploid hyphae can be obtained by inoculation of potato sucrose broth in shaker incubation at 130 rpm, 20?for 14-20 days. This technique was effective in obtaining monokaryotic haploid hyphae for all 20 isolates of U. segetum var. tritici.
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