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Pathway Regulation (pathway + regulation)
Selected AbstractsWnt Pathway Regulation in Chronic Renal Allograft DamageAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2009C. Von Toerne The Wnt signaling pathway, linked to development, has been proposed to be recapitulated during the progressive damage associated with chronic organ failure. Chronic allograft damage following kidney transplantation is characterized by progressive fibrosis and a smoldering inflammatory infiltrate. A modified, Fischer 344 (RT1lvl) to Lewis (RT1l) rat renal allograft model that reiterates many of the major pathophysiologic processes seen in patients with chronic allograft failure was used to study the progressive disease phenotype and specific gene product expression by immunohistochemistry and transcriptomic profiling. Central components of the Tgfb, canonical Wnt and Wnt-Ca2+ signaling pathways were significantly altered with the development of chronic damage. In the canonical Wnt pathway, Wnt3, Lef1 and Tcf1 showed differential regulation. Target genes Fn1, Cd44, Mmp7 and Nos2 were upregulated and associated with the progression of renal damage. Changes in the Wnt-Ca2+ pathway were evidenced by increased expression of Wnt6, Wnt7a, protein kinase C, Cam Kinase II and Nfat transcription factors and the target gene vimentin. No evidence for alterations in the Wnt planar cell polarity (PCP) pathway was detected. Overall results suggest cross talk between the Wnt and Tgfb signaling pathways during allograft inflammatory damage and present potential targets for therapeutic intervention. [source] Xenopus axin-related protein: A link between its centrosomal localization and function in the Wnt/,-catenin pathwayDEVELOPMENTAL DYNAMICS, Issue 1 2010Evguenia M. Alexandrova Abstract The Wnt/,-catenin signaling pathway regulates cell proliferation and cell fate determination in multiple systems. However, the subcellular localization of Wnt pathway components and the significance of this localization for the pathway regulation have not been extensively analyzed. Here we report that Xenopus Axin-related protein (XARP), a component of the ,-catenin destruction complex, is localized to the centrosome. This localization of XARP requires the presence of the DIX domain and an adjacent region. Since other components of the Wnt pathway have also been shown to associate with the centrosome, we tested a hypothesis that the ,-catenin destruction complex operates at the centrosome. However, XARP mutants with poor centrosomal localization revealed an enhanced rather than decreased ability to antagonize the Wnt/,-catenin pathway. Our data are consistent with the idea that the inactivation of XARP at the centrosome is an important regulatory point in Wnt signaling. Developmental Dynamics 239:261,270, 2010. © 2009 Wiley-Liss, Inc. [source] Genotype,phenotype correlations in hereditary familial retinoblastoma,HUMAN MUTATION, Issue 3 2007Melissa Taylor Abstract We studied 50 unrelated pedigrees with a family history of retinoblastoma (Rb) (165 carriers of a RB1 mutation) to delineate the spectrum of RB1 germline mutations in familial Rb and to identify genotype,phenotype correlations as well as putative modifiers. Patients were followed at Institut Curie and they were examined by an ophthalmologist, a pediatrician, and a geneticist. All cases of familial Rb were determined via genetic counseling. Clinical features included disease status, laterality, age at diagnosis, mutation type, follow-up, and disease,eye ratio (DER). To eliminate mosaic cases, first-generation carriers displaying low-penetrance (LP) Rb were excluded from the analysis. Complete penetrance was the rule for nonsense and frameshift mutations (25 families) and high penetrance was observed for large rearrangements (eight families). Promoter (two families) and missense (two families) mutations displayed heterogeneous phenotypes and LP. Variable penetrance was observed for splice abnormalities (13 families) and was explained by in/out of frame mutations or respect of functional domains. Surprisingly, two families with the LP g.45867G>T/IVS6+1G>T mutation presented data that conflicted with the data reported in previous publications, as unaffected carriers had paternally inherited mutant alleles. Moreover, RNA analyses suggested that the lack of penetrance in unaffected carriers could be explained by an increase in expression levels of the wild-type allele. This observation prompted us to define a new class "3" of LP alleles. We believe this is the first large-scale study of familial Rb with a high level of homogeneity in the clinical and genetic analysis of patients and their relatives, thereby allowing for reliable intrafamilial genotype,phenotype correlations. Our analysis suggests in some cases the influence of modifier factors probably involved in mRNA level regulation and/or pRB pathway regulation. Hum Mutat 28(3), 284,293, 2007. © 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] A new holistic exploratory approach to Systems Biology by Near Infrared Spectroscopy evaluated by chemometrics and data inspectionJOURNAL OF CHEMOMETRICS, Issue 10-11 2007Lars Munck Abstract There is a need for an improved biological and theoretical interpretation of Near Infra-Red Spectral (NIRS) fingerprints from tissues that could contribute with holistic overview to fine-grained detail modelled in Systems Biology. The concept of gene expression in self-organised networks was experimentally tested in a barley endosperm model with molecularly defined and undefined mutants. Surprisingly reproducible gene-specific NIRS fingerprints were observed directly in log1/R MSC pre-treated spectra that could not be accurately represented by destructive mathematical models. A mutant spectrum in an isogenic background represents the physiochemical expression of the gene in the whole network (tissue). The necessary holistic overview that is needed experimentally to introduce Ilya Prigogine's theory on self-organisation in Systems Biology was supplied by defining the spectral phenome. Interval spectral information on genotypes and environment was classified by interval Extended Canonical Variates Analysis (iECVA). Genetic changes in spectra were interpreted by interval Partial Least Squares Regression (iPLSR) correlations to chemical variables. A new pathway regulation was detected. The finely grained ,bottom up' modelling of molecular and chemical data from pathways requires a coarsely grained exploratory ,top down' overview by NIRS to account for the outcome of self-organisation. The amplification of expression from a gene to the phenome (pleiotropy) can now for the first time be quantified as a whole reproducible phenomenological pattern by NIRS and compared to other gene spectra. It explains published findings that transformed respectively mutated genes in genetically modified organisms (GMOs) and cancer patients can be detected unsupervised from tissues by spectroscopy, chemometrics and data inspection. Copyright © 2007 John Wiley & Sons, Ltd. [source] | |||||||||||||