|
| ||
|
|
||
Biological Pathways (biological + pathway)
Selected AbstractsTannerella forsythia infection-induced calvarial bone and soft tissue transcriptional profilesMOLECULAR ORAL MICROBIOLOGY, Issue 5 2010V. Bakthavatchalu Summary Tannerella forsythia is associated with subgingival biofilms in adult periodontitis, although the molecular mechanisms contributing to chronic inflammation and loss of periodontal bone remain unclear. We examined changes in the host transcriptional profiles during a T. forsythia infection using a murine calvarial model of inflammation and bone resorption. Tannerella forsythia was injected into the subcutaneous soft tissue over calvariae of BALB/c mice for 3 days, after which the soft tissues and calvarial bones were excised. RNA was isolated and Murine GeneChip® (Affymetrix, Santa Clara, CA) array analysis of transcript profiles showed that 3226 genes were differentially expressed in the infected soft tissues (P < 0.05) and 2586 genes were differentially transcribed in calvarial bones after infection. Quantitative real-time reverse transcription-polymerase chain reaction analysis of transcription levels of selected genes corresponded well with the microarray results. Biological pathways significantly impacted by T. forsythia infection in calvarial bone and soft tissue included leukocyte transendothelial migration, cell adhesion molecules (immune system), extracellular matrix,receptor interaction, adherens junction, and antigen processing and presentation. Histologic examination revealed intense inflammation and increased osteoclasts in calvariae compared with controls. In conclusion, localized T. forsythia infection differentially induces transcription of a broad array of host genes, and the profiles differ between inflamed soft tissues and calvarial bone. [source] Molecular characterization of Treponema denticola infection-induced bone and soft tissue transcriptional profilesMOLECULAR ORAL MICROBIOLOGY, Issue 4 2010V. Bakthavatchalu Summary Treponema denticola is associated with subgingival biofilms in adult periodontitis and with acute necrotizing ulcerative gingivitis. However, the molecular mechanisms by which T. denticola impacts periodontal inflammation and alveolar bone resorption remain unclear. Here, we examined changes in the host transcriptional profiles during a T. denticola infection using a murine calvarial model of inflammation and bone resorption. T. denticola was injected into the subcutaneous soft tissue over the calvaria of BALB/c mice for 3 days, after which the soft tissues and the calvarial bones were excised. RNA was isolated and analysed for transcript profiling using Murine GeneChip® arrays. Following T. denticola infection, 2905 and 1234 genes in the infected calvarial bones and soft tissues, respectively, were differentially expressed (P , 0.05). Biological pathways significantly impacted by T. denticola infection in calvarial bone and calvarial tissue included leukocyte transendothelial migration, cell adhesion (immune system) molecules, cell cycle, extracellular matrix,receptor interaction, focal adhesion, B-cell receptor signaling and transforming growth factor-, signaling pathways resulting in proinflammatory, chemotactic effects, and T-cell stimulation. In conclusion, localized T. denticola infection differentially induces transcription of a broad array of host genes, the profiles of which differed between inflamed calvarial bone and soft tissues. [source] Netrin-G2 and netrin-G2 ligand are both required for normal auditory responsivenessGENES, BRAIN AND BEHAVIOR, Issue 4 2008W. Zhang Mice in which netrin-G2 has been genetically inhibited do not startle to an acoustic stimulus, but otherwise perform normally through a behavioral test battery. Light microscopic examination of the inner ear showed no obvious structural abnormalities. Brainstem responses to acoustic stimuli (auditory brainstem responses, ABR) were also present, confirming the lack of any overarching defects in the inner ear or auditory nerve. Genetic inhibition of netrin-G2 ligand produced a nearly identical phenotype, that is, no startle with ABR present, and otherwise normal. This similarity confirms that these two proteins act in the same biological pathway. We have also determined that the affinity between the two proteins is strong, around 2.5 nm, similar to that observed between netrin-G1 and netrin-G1 ligand , 2.3 nm in our hands. The combination of equivalent phenotypes when genetically inhibited coupled with evidence of a strong biochemical interaction supports the notion of a receptor,ligand interaction between these two proteins in vivo. This interaction is critical for auditory synaptic responsiveness in the brain. [source] Association tests using kernel-based measures of multi-locus genotype similarity between individualsGENETIC EPIDEMIOLOGY, Issue 3 2010Indranil Mukhopadhyay Abstract In a genetic association study, it is often desirable to perform an overall test of whether any or all single-nucleotide polymorphisms (SNPs) in a gene are associated with a phenotype. Several such tests exist, but most of them are powerful only under very specific assumptions about the genetic effects of the individual SNPs. In addition, some of the existing tests assume that the direction of the effect of each SNP is known, which is a highly unlikely scenario. Here, we propose a new kernel-based association test of joint association of several SNPs. Our test is non-parametric and robust, and does not make any assumption about the directions of individual SNP effects. It can be used to test multiple correlated SNPs within a gene and can also be used to test independent SNPs or genes in a biological pathway. Our test uses an analysis of variance paradigm to compare variation between cases and controls to the variation within the groups. The variation is measured using kernel functions for each marker, and then a composite statistic is constructed to combine the markers into a single test. We present simulation results comparing our statistic to the U -statistic-based method by Schaid et al. ([2005] Am. J. Hum. Genet. 76:780,793) and another statistic by Wessel and Schork ([2006] Am. J. Hum. Genet. 79:792,806). We consider a variety of different disease models and assumptions about how many SNPs within the gene are actually associated with disease. Our results indicate that our statistic has higher power than other statistics under most realistic conditions. Genet. Epidemiol. 34: 213,221, 2010. © 2009 Wiley-Liss, Inc. [source] dTrf2 is required for transcriptional and developmental responses to ecdysone during Drosophila metamorphosisDEVELOPMENTAL DYNAMICS, Issue 11 2007Arash Bashirullah Abstract The TATA box-binding protein (TBP) related factor 2 (TRF2) has been well characterized at a biochemical level and in cultured cells. Relatively little, however, is known about how TRF2 functions in specific biological pathways during development. Here, we show that Drosophila TRF2 (dTRF2) plays an essential role in responses to the steroid hormone ecdysone during the onset of metamorphosis. Hypomorphic dTrf2 mutations lead to developmental arrest during prepupal and early pupal stages with defects in major ecdysone-triggered biological responses, including puparium formation, anterior spiracle eversion, gas bubble translocation, adult head eversion, and larval salivary gland cell death. The transcription of key ecdysone-regulated target genes is delayed and reduced in dTrf2 mutants. dTrf2 appears to be required for the proper timing and levels of ecdysone-regulated gene expression required for entry into metamorphosis. Developmental Dynamics 236:3173,3179, 2007. © 2007 Wiley-Liss, Inc. [source] A polygenic model for integration of linkage and pathway informationGENETIC EPIDEMIOLOGY, Issue 3 2009J.J.P. Lebrec Abstract We introduce an approximate model for linkage curves which accommodates the polygenic structure of complex diseases and accounts for the simultaneous action of closely located genes. The model is extended so that information on biological pathways can be integrated. Using data on rheumatoid arthritis, we describe some of the many applications which the model allows: it can be used to test for residual linkage in the presence of already established loci, to derive a global test for linkage, to test for the relevance of a gene list in terms of linkage and to help in candidate gene prioritization by integration of gene-pathway annotation data. Genet. Epidemiol. 2009. © 2008 Wiley-Liss, Inc. [source] Summary of contributions to GAW15 Group 16: Processing/normalization of expression traitsGENETIC EPIDEMIOLOGY, Issue S1 2007Aurélie Labbe Abstract Here, we summarize the contributions to group 16 of Genetic Analysis Workshop 15, held in Florida, U.S.A. The theme of this group was preprocessing of expression quantitative trait loci (eQTL) studies using the Affymetrix platform. The objective of the Genetic Analysis Workshop 15 problem 1 dataset was to use transcript levels that are measured using DNA microarrays as quantitative traits and localize the genes or other features of the DNA that control gene expression by quantitative trait loci linkage analyses. All contributors of this group used the microarray expression profiles (problem 1) data. Various approaches and questions were examined to investigate the effects of preprocessing methods and/or gene filtering on the interpretation of data, specifically on heritability estimates of gene expression and on linkage results. In addition, some contributors focused on the statistical issues involved in large-scale genetic analyses of quantitative traits that account for or build composite phenotypes from a large number of correlated traits. Since the true eQTLs are not known in the problem 1 data, results from the 11 studies cannot be fully evaluated for the methods employed. However, several common trends were found. All reports concluded that preprocessing statistical analyses may have an important impact on eQTL analyses and on the identification of cis -/trans -regulators and/or major biological pathways. Genet. Epidemiol. 31(Suppl. 1):S132,S138, 2007. © 2007 Wiley-Liss, Inc. [source] A gene-alteration profile of human lung cancer cell lines,HUMAN MUTATION, Issue 8 2009Raquel Blanco Abstract Aberrant proteins encoded from genes altered in tumors drive cancer development and may also be therapeutic targets. Here we derived a comprehensive gene-alteration profile of lung cancer cell lines. We tested 17 genes in a panel of 88 lung cancer cell lines and found the rates of alteration to be higher than previously thought. Nearly all cells feature inactivation at TP53 and CDKN2A or RB1, whereas BRAF, MET, ERBB2, and NRAS alterations were infrequent. A preferential accumulation of alterations among histopathological types and a mutually exclusive occurrence of alterations of CDKN2A and RB1 as well as of KRAS, epidermal growth factor receptor (EGFR), NRAS, and ERBB2 were seen. Moreover, in non-small-cell lung cancer (NSCLC), concomitant activation of signal transduction pathways known to converge in mammalian target of rapamycin (mTOR) was common. Cells with single activation of ERBB2, PTEN, or MET signaling showed greater sensitivity to cell-growth inhibition induced by erlotinib, LY294002, and PHA665752, respectively, than did cells featuring simultaneous activation of these pathways, underlining the need for combined therapeutic strategies in targeted cancer treatments. In conclusion, our gene-alteration landscape of lung cancer cell lines provides insights into how gene alterations accumulate and biological pathways interact in cancer. Hum Mutat 30,1,8, 2009. © 2009 Wiley-Liss, Inc. [source] Ala394Thr polymorphism in the clock gene NPAS2: A circadian modifier for the risk of non-Hodgkin's lymphomaINTERNATIONAL JOURNAL OF CANCER, Issue 2 2007Yong Zhu Abstract Circadian disruption is theorized to cause immune dysregulation, which is the only established risk factor for non-Hodgkin's lymphoma (NHL). Genes responsible for circadian rhythm are also involved in cancer-related biological pathways as potential tumor suppressors. However, no previous studies have examined associations between circadian genes and NHL risk. In this population-based case control study (n = 455 cases; 527 controls), we examined the only identified nonsynonymous polymorphism (Ala394Thr; rs2305160) in the largest circadian gene, neuronal PAS domain protein 2 (NPAS2), in order to examine its impact on NHL risk. Our results demonstrate a robust association of the variant Thr genotypes (Ala/Thr and Thr/Thr) with reduced risk of NHL (OR = 0.66, 95% CI: 0.51,0.85, p = 0.001), especially B-cell lymphoma (OR = 0.61, 95% CI: 0.47,0.80, p ,, 0.0001). These findings provide the first molecular epidemiologic evidence supporting a role of circadian genes in lymphomagenesis, which suggests that genetic variations in circadian genes might be a novel panel of promising biomarkers for NHL and warrants further investigation. © 2006 Wiley-Liss, Inc. [source] Comparative analysis of global gene expression profiles between diabetic rat wounds treated with vacuum-assisted closure therapy, moist wound healing or gauze under suctionINTERNATIONAL WOUND JOURNAL, Issue 5 2008Kathleen L Derrick Abstract How differential gene expression affects wound healing is not well understood. In this study, Zucker diabetic fatty (fa/fa) male inbred rats were used to investigate gene expression during wound healing in an impaired wound-healing model. Whole genome microarray surveys were used to gain insight into the biological pathways and healing processes in acute excisional wounds treated with vacuum-assisted closure (V.A.C.®) Therapy, moist wound healing (MWH) or gauze under suction (GUS). Global gene expression analyses after 2 days of healing indicated major differences with respect to both number of genes showing fold changes and pathway regulation between the three different wound treatments. Statistical analysis of expression profiles indicated that 5072 genes showed a >1·6-fold change with V.A.C. Therapy compared with 3601 genes with MWH and 3952 genes with GUS. Pathways and related genes associated with the early phases of wound healing diverged between treatment groups. For example, pathways involving angiogenesis, cytoskeletal regulation and inflammation were associated with elevated gene expression following V.A.C. Therapy. This study is the first to assess wound healing by whole genome interrogation in a diabetic rat model treated with different healing modalities. [source] New technologies for chemical geneticsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue S37 2001Leslie A. Walling Abstract Chemical genetics, in which small molecules are used in lieu of mutations to study biological processes, requires large and diverse chemical libraries to specifically perturb different biological pathways. Here we describe a suite of technologies that enable chemical libraries prepared by split-pool solid phase synthesis to be screened in a diverse range of chemical genetic assays. Compounds are synthesized on 500 micron high-capacity polystyrene beads, and arrayed into individual wells of 384-well plates using a hand-held bead arrayer. Compounds are cleaved from synthesis beads using a chemically-resistant ceramic dispensing system, producing individual stock solutions of single compounds. Nanoliter volumes of these solutions are then transferred into assay plates using an array of stainless steel pins mounted on a robotic arm. We have designed reusable 1536- and 6144-well assay plates made of silicone rubber that can be cast in the laboratory and filled by hand. This integrated technology platform enables hundreds of biological assays to be performed from the product of a single synthesis bead, enabling the results of different chemical genetic experiments to be directly compared. J. Cell. Biochem. Suppl. 37: 7,12, 2001. © 2002 Wiley-Liss, Inc. [source] Review: Recent progress in frontotemporal lobar degenerationNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 1 2010S. M. Pickering-Brown S. M. Pickering-Brown (2010) Neuropathology and Applied Neurobiology36, 4,16 Recent progress in frontotemporal lobar degeneration Frontotemporal lobar degeneration (FTLD) is a highly familial condition and is increasingly being recognized as an important form of dementia. The literature published on this disease is often difficult to collate due to the wide range in nomenclature used. Thankfully, consensus recommendations have now been published to address this issue and hopefully the community will adopt these as intended. Much progress has been made in our understanding of the clinical, pathological and genetic understanding of FTLD in recent years. Progranulin and TDP-43 have recently been identified as new important proteins involved in the pathophysiology of FTLD and this latter protein may have potential as a biomarker of this disease. However, much remains before we have a full picture of the genes that cause FTLD and the biological pathways in which they function. The purpose of this review is to summarize the current concepts and recent advances in our knowledge of this disease. [source] Developmental vitamin D deficiency alters brain protein expression in the adult rat: Implications for neuropsychiatric disordersPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 5 2007Lionel Almeras Abstract An increased risk for multiple sclerosis and schizophrenia is observed at increasing latitude and in patients born in winter or spring. To explore a possible link between maternal vitamin D deficiency and these brain disorders, we examined the impact of prenatal hypovitaminosis D on protein expression in the adult rat brain. Vitamin D-deficient female rats were mated with vitamin D normal males. Pregnant females were kept vitamin D-deficient until birth whereupon they were returned to a control diet. At week 10, protein expression in the progeny's prefrontal cortex and hippocampus was compared with control animals using silver staining 2-D gels associated with MS and newly devised data mining software. Developmental vitamin D (DVD) deficiency caused a dysregulation of 36 brain proteins involved in several biological pathways including oxidative phosphorylation, redox balance, cytoskeleton maintenance, calcium homeostasis, chaperoning, PTMs, synaptic plasticity and neurotransmission. A computational analysis of these data revealed that (i) nearly half of the molecules dysregulated in our animal model have also been shown to be misexpressed in either schizophrenia and/or multiple sclerosis and (ii) an impaired synaptic network may be a consequence of mitochondrial dysfunction. [source] Transcriptome profiling of cotton-bollworm larvae fed on transgenic hpa1Xoo cotton leaves by the application of silkworm 23K oligo microarrayANNALS OF APPLIED BIOLOGY, Issue 1 2010W. Miao To analyse the resistance of harpinXoo -expressing transgenic cotton T-34 plants to cotton-bollworm (Helicoverpa armigera), bioassays and the silkworm genome-wide microarray were employed. The global transcriptomic level was used to compare the H. armigera larvae fed on T-34 leaves (LFT-34) with larvae fed on leaves of the untransformed cotton line Z35 (LFZ35). The development of LFT-34 was slowed, eventually leading to larval death. The microarray data indicated that 872 genes in LFT-34 were totally deregulated, comparing to their expression in LFZ35. All the preferentially expressed genes were classified into 13 biological functions and were involved in 96 biological pathways. These results indicated that harpinXoo confers T-34 with resistance to H. armigera and influences multiple metabolic pathways in the larvae. Hpa1Xoo, as a new genetic resource, provides primary evidence for breeding cotton that is resistant to cotton bollworm. The results also showed that the silkworm 70-mer oligo microarray can be used as a new approach to analyse the global transcriptional expression of H. armigera and its interaction with plants. [source] U-Statistics-based Tests for Multiple Genes in Genetic Association StudiesANNALS OF HUMAN GENETICS, Issue 6 2008Zhi Wei Summary As our understanding of biological pathways and the genes that regulate these pathways increases, consideration of these biological pathways has become an increasingly important part of genetic and molecular epidemiology. Pathway-based genetic association studies often involve genotyping of variants in genes acting in certain biological pathways. Such pathway-based genetic association studies can potentially capture the highly heterogeneous nature of many complex traits, with multiple causative loci and multiple alleles at some of the causative loci. In this paper, we develop two nonparametric test statistics that consider simultaneously the effects of multiple markers. Our approach, which is based on data-adaptive U-statistics, can handle both qualitative data such as case-control data and quantitative continuous phenotype data. Simulations demonstrate that our proposed methods are more powerful than standard methods, especially when there are multiple risk loci each with small genetic effects. When the number of disease-predisposing genes is small, the data-adaptive weighting of the U-statistics over all the markers produces similar power to commonly used single marker tests. We further illustrate the potential merits of our proposed tests in the analysis of a data set from a pathway-based candidate gene association study of breast cancer and hormone metabolism pathways. Finally, potential applications of the proposed tests to genome-wide association studies are also discussed. [source] The organic chemistry of biological pathways: McMurry, John, and Begley, TadhgBIOCHEMISTRY AND MOLECULAR BIOLOGY EDUCATION, Issue 5 2005Frank Vella No abstract is available for this article. [source] Incorporating Predictor Network in Penalized Regression with Application to Microarray DataBIOMETRICS, Issue 2 2010Wei Pan Summary We consider penalized linear regression, especially for "large,p, small,n" problems, for which the relationships among predictors are described a priori by a network. A class of motivating examples includes modeling a phenotype through gene expression profiles while accounting for coordinated functioning of genes in the form of biological pathways or networks. To incorporate the prior knowledge of the similar effect sizes of neighboring predictors in a network, we propose a grouped penalty based on the,L, -norm that smoothes the regression coefficients of the predictors over the network. The main feature of the proposed method is its ability to automatically realize grouped variable selection and exploit grouping effects. We also discuss effects of the choices of the , and some weights inside the,L, -norm. Simulation studies demonstrate the superior finite-sample performance of the proposed method as compared to Lasso, elastic net, and a recently proposed network-based method. The new method performs best in variable selection across all simulation set-ups considered. For illustration, the method is applied to a microarray dataset to predict survival times for some glioblastoma patients using a gene expression dataset and a gene network compiled from some Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. [source] Using gene chips to identify organ-specific, smooth muscle responses to experimental diabetes: potential applications to urological diseasesBJU INTERNATIONAL, Issue 2 2007Jason D. Hipp OBJECTIVE To identify early diabetes-related alterations in gene expression in bladder and erectile tissue that would provide novel diagnostic and therapeutic treatment targets to prevent, delay or ameliorate the ensuing bladder and erectile dysfunction. MATERIALS AND METHODS The RG-U34A rat GeneChip® (Affymetrix Inc., Sunnyvale, CA, USA) oligonucleotide microarray (containing ,8799 genes) was used to evaluate gene expression in corporal and male bladder tissue excised from rats 1 week after confirmation of a diabetic state, but before demonstrable changes in organ function in vivo. A conservative analytical approach was used to detect alterations in gene expression, and gene ontology (GO) classifications were used to identify biological themes/pathways involved in the aetiology of the organ dysfunction. RESULTS In all, 320 and 313 genes were differentially expressed in bladder and corporal tissue, respectively. GO analysis in bladder tissue showed prominent increases in biological pathways involved in cell proliferation, metabolism, actin cytoskeleton and myosin, as well as decreases in cell motility, and regulation of muscle contraction. GO analysis in corpora showed increases in pathways related to ion channel transport and ion channel activity, while there were decreases in collagen I and actin genes. CONCLUSIONS The changes in gene expression in these initial experiments are consistent with the pathophysiological characteristics of the bladder and erectile dysfunction seen later in the diabetic disease process. Thus, the observed changes in gene expression might be harbingers or biomarkers of impending organ dysfunction, and could provide useful diagnostic and therapeutic targets for a variety of progressive urological diseases/conditions (i.e. lower urinary tract symptoms related to benign prostatic hyperplasia, erectile dysfunction, etc.). [source] Cell-Permeable ,-Peptide Inhibitors of p53/hDM2 ComplexationCHEMBIOCHEM, Issue 6 2009Elizabeth A. Harker Abstract Look at what the cat(ionic motif) dragged in! We report a general strategy to increase the cell permeability of ,3 -peptides. Introduction of a minimal cationic motif within the folded structure of a high-affinity ,3 -peptide ligand for hDM2 led to molecules with high 314 -helical structure, high hDM2 affinity and sufficient cell permeability to upregulate p53-dependent genes in live mammalian cells. Minimally cationic ,3 -peptides represent the critical first step towards a class of protease-resistant peptidomimetics that might modulate intracellular biological pathways. [source] 4142: The Sanger Mouse Genetics Programme: high throughput characterisation of knockout miceACTA OPHTHALMOLOGICA, Issue 2010AK GERDIN Purpose The Sanger Mouse Genetics Programme (MGP) aims to make a significant impact on our understanding of the function of genes and their role in disease by generating, characterising and archiving in the order of 200 lines of knockout mice per year, including 40 lines as part of the EUMODIC consortium. The phenotyping screens employed include a wide range of assays relevant to key disease areas including diabetes, obesity, hearing and vision disorders, immune disorders, pain and motor function. The data generated by the primary screen will help to further the understanding of the interplay of genes and disease and will provide an insight into the various underlying biological pathways. All phenotyping data and biological resources generated by the programme are openly available to the scientific community. Methods Eye morphology is routinely assessed using the Slit Lamp and Ophthalmoscope and images are collected when abnormalities are identified. Expression profiling via the lacZ reporter gene is performed for each mutant line in adults and at E14.5. Results To date, the eye screen has been performed on over 180 mutant lines. Here we report examples of novel eye-related abnormalities identified by the eye morphology, embryonic lethality and/or expression screens performed by the Sanger MGP. We will present how to identify a potentially interesting mouse mutant on our database and discuss the impact our knock-out mouse models might have on your research. [source] 1,3,5-Triazepan-2,6-diones as Structurally Diverse and Conformationally Constrained Dipeptide Mimetics: Identification of Malaria Liver Stage Inhibitors from a Small Pilot LibraryCHEMISTRY - A EUROPEAN JOURNAL, Issue 33 2006Gersande Lena Abstract The development of the 1,3,5-triazepan-2,6-dione system as a novel, conformationally restricted, and readily accessible class of dipeptidomimetics is reported. The synthesis of the densely functionalized 1,3,5-triazepan-2,6-dione skeleton was achieved in only four steps from a variety of simple linear dipeptide precursors. To extend the practical value of 1,3,5-triazepane-2,6-diones, a general polymer-assisted solution-phase synthesis approach amenable to library production in a multiparallel format was developed. The conformational preferences of the 1,3,5-triazepan-2,6-dione skeleton were investigated in detail by NMR spectroscopy and X-ray diffraction. The ring exhibits a characteristic folded conformation which was compared to that of related dipeptide-derived scaffolds including the more planar 2,5-diketopiperazine (DKP). Molecular and structural diversity was increased further through post-cyclization appending operations at urea nitrogens. Preliminary biological screens of a small collection of 1,3,5-triazepan-2,6-diones revealed inhibitors of the underexplored malaria liver stage and suggest strong potential for this dipeptide-derived scaffold to interfere with and to modulate biological pathways. [source] Using gene chips to identify organ-specific, smooth muscle responses to experimental diabetes: potential applications to urological diseasesBJU INTERNATIONAL, Issue 2 2007Jason D. Hipp OBJECTIVE To identify early diabetes-related alterations in gene expression in bladder and erectile tissue that would provide novel diagnostic and therapeutic treatment targets to prevent, delay or ameliorate the ensuing bladder and erectile dysfunction. MATERIALS AND METHODS The RG-U34A rat GeneChip® (Affymetrix Inc., Sunnyvale, CA, USA) oligonucleotide microarray (containing ,8799 genes) was used to evaluate gene expression in corporal and male bladder tissue excised from rats 1 week after confirmation of a diabetic state, but before demonstrable changes in organ function in vivo. A conservative analytical approach was used to detect alterations in gene expression, and gene ontology (GO) classifications were used to identify biological themes/pathways involved in the aetiology of the organ dysfunction. RESULTS In all, 320 and 313 genes were differentially expressed in bladder and corporal tissue, respectively. GO analysis in bladder tissue showed prominent increases in biological pathways involved in cell proliferation, metabolism, actin cytoskeleton and myosin, as well as decreases in cell motility, and regulation of muscle contraction. GO analysis in corpora showed increases in pathways related to ion channel transport and ion channel activity, while there were decreases in collagen I and actin genes. CONCLUSIONS The changes in gene expression in these initial experiments are consistent with the pathophysiological characteristics of the bladder and erectile dysfunction seen later in the diabetic disease process. Thus, the observed changes in gene expression might be harbingers or biomarkers of impending organ dysfunction, and could provide useful diagnostic and therapeutic targets for a variety of progressive urological diseases/conditions (i.e. lower urinary tract symptoms related to benign prostatic hyperplasia, erectile dysfunction, etc.). [source] | |||||||||||||||||||