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Results for “Potential modifier genes”

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At least 739 records · Page 41Linked to original sources
PubMed2003

Characterization of the human glycerol kinase promoter: identification of a functional HNF-4alpha binding site and evidence for transcriptional activation.

Glycerol kinase (GK) is an enzyme at the interface of carbohydrate and fat metabolism. Mutations in the GK gene result in a rare inborn error of metabolism, GK deficiency (GKD), and at least one of these mutations (N288D) is associated with insulin resistance and diabetes mellitus. In an attempt to identify potential modifiers of the GKD phenotype, and to elucidate better the relationship between GKD and diabetes mellitus, we investigated the GK promoter. We examined the GK promoter using in silico methods, transient transfections of GK promoter-luciferase constructs in HepG2 hepatocellular carcinoma cells, and gel shift assays using liver nuclear extracts. We determined that the first 100 bp of the GK 5(') upstream region was sufficient for basal levels of transcription and that there was a functional HNF-4alpha binding site in the first 500 bp of the 5(') upstream region that was important for increased levels of GK expression in vitro. The involvement of both GK and HNF-4alpha in the etiology of diabetes mellitus is intriguing, and we speculate that HNF-4alpha represents a potential modifier of the GKD phenotype.

5' Flanking Region↗
PubMed1998

Implication of alpha1-antichymotrypsin polymorphism in familial Alzheimer's disease.

A common polymorphism in the alpha1-antichymotrypsin (ACT) gene has been shown to modify the Apolipoprotein E (ApoE) epsilon4-associated Alzheimer's disease (AD) risk identifying the combination of the ACT/AA and ApoE epsilon4/epsilon4 genotypes as a potential susceptibility marker for AD. Using the polymerase chain reaction, we analyzed the segregation of the ACT and ApoE polymorphisms in familial Alzheimer's disease (FAD) patients carrying mutations in Presenilin (PS) and APP genes and in both early onset (EO) and late onset (LO) FAD patients without known mutations. Our data suggest that ACT does not represent an additional risk factor for PS and APP mutated families. However, in LOFAD patients a high frequency of the combined ACT/AA and ApoE epsilon4/epsilon4 genotypes suggest that ACT may interact with ApoE and play a role in LOFAD.

Adult↗
PubMed2004

Antisense approaches in prostate cancer.

Patients with hormone refractory prostate cancer have limited treatment options and new therapies are urgently needed. Advances in the understanding of the molecular mechanisms implicated in prostate cancer progression have identified many potential therapeutic gene targets that are involved in apoptosis, growth factors, cell signalling and the androgen receptor (AR). Antisense oligonucleotides are short sequences of synthetic modified DNA that are designed to be complimentary to a selected gene's mRNA and thereby specifically inhibit expression of that gene. The antisense approach continues to hold promise as a therapeutic modality to target genes involved in cancer progression, especially those in which the gene products are not amenable to small molecule inhibition or antibodies. The current status and future direction of a number of antisense oligonucleotides targeting several genes, including BCL-2, BCL-XL, clusterin, the inhibitors of apoptosis (IAP) family, MDM2, protein kinase C-alpha, c-raf, insulin-like growth factor binding proteins and the AR, that have potential clinical use in prostate cancer are reviewed.

Apoptosis↗
PubMed2002

A preliminary investigation of modified alginates as a matrix for gene transfection in a HeLa cell model.

Previous reports have demonstrated the effectiveness of chitosan as a transfection agent. These studies have noted the importance of polysaccharide backbone interactions with the cell surface as well as cationic groups in the transfection process. The present study focuses upon the potential utility of another polysaccharide hydrogel, alginic acid, as a transfection agent. Alginic acid was modified by carbodiimide-mediated linkage of several heterocyclic and aromatic amines to the carboxyl group of the alginate, giving the alginate polycationic characteristics through which binding to nucleic acids could be facilitated. The amines used for this modification include diaminoacridine, thionin, basic fuchsin, acridine yellow, and diaminomethyltriazine. Of all the conjugates tested, basic fuchsin-modified alginate produced the greatest increase in the transfection of a plasmid coding for beta-galactosidase into HeLa cells. These studies demonstrate that other polysaccharide hydrogels can be used as transfection agents, and the structural orientation of the cationic spacer arm is crucial for effective transfection.

Alginates↗
PubMed1992

Transcriptional regulation of the human cholesterol 7 alpha-hydroxylase gene.

As an initial step toward understanding the transcriptional regulation of cholesterol 7 alpha-hydroxylase (CYP7) in man, we isolated and functionally characterized the 5'-flanking region of the human CYP7 gene. The nucleotide sequences of the first exon and 1.6 kb preceding the exon were determined and found to contain a TATA box at position -30, a modified CAAT box at position -92, three potential hepatocyte nuclear factor 3 (HNF-3) recognition sites at nucleotides -316, -288, and -255, respectively, and a modified sterol response element at position -271. DNA sequences containing 1.3 kb of the 5'-flanking region and 29 nucleotides of the first exon were linked to the chloramphenicol acetyltransferase gene and transiently transfected into several cell lines. Promoter activity was very strong in the human hepatoma cell line HepG2 but absent in cells of nonhepatic origin. Mutational analysis of the promoter identified several regions that function in the transcriptional regulation of CYP7. Introduction of a fragment containing the region from -432 to -220 upstream of a heterologous promoter, in either orientation, resulted in a tremendous stimulation of activity in HepG2 cells. DNase I footprint analysis identified three regions within this fragment which were protected from digestion. The overexpression of HNF-3 in HepG2 cells resulted in a 4-fold stimulation of CYP7 transcriptional activity. We suggest that the region between -432 and -220 functions as a cell-specific enhancer whose activity is controlled, in part, by HNF-3.

Amino Acid Sequence↗
PubMed2004

Cationic silica nanoparticles as gene carriers: synthesis, characterization and transfection efficiency in vitro and in vivo.

The potential of cationic SiO2 nanoparticles was investigated for in vivo gene transfer in this study. Cationic SiO2 nanoparticles with surface modification were generated using amino-hexyl-amino-propyltri-methoxysilane (AHAPS). The zeta potential of the nanoparticles at pH = 7.4 varied from -31.4 mV (unmodified particles; 10 nm) to +9.6 mV (modified by AHAPS). Complete immobilization of DNA at the nanoparticle surface was achieved at a particle ratio of 80 (w/w nanoparticle/DNA ratio). The surface modified nanoparticle had a size of 42 nm with a distribution from 10-100 nm. The ability of these particles to transfect pCMVbeta reporter gene was tested in Cos-1 cells, and optimum results were obtained in the presence of FCS and chloroquine at a particle ratio of 80. These nanoparticles were tested for their ability to transfer genes in vivo in the mouse lung, and a two-times increase in the expression levels was found with silica particles in comparison to EGFP alone. Very low or no cell toxicity was observed, suggesting silica nanoparticles as potential alternatives for gene transfection.

Animals↗
PubMed1998

Control of erythropoietin delivery by doxycycline in mice after intramuscular injection of adeno-associated vector.

We reported previously that controlled expression of a foreign gene in response to tetracycline derivative can be accomplished in mice by the autologous transplantation of retrovirus-modified muscle cells. Although regulated systemic delivery of therapeutic proteins from engineered tissues has potential clinical application, the transplantation of muscle cells is not currently feasible in humans. Several studies have shown that a single injection of adeno-associated virus (AAV) vectors into mouse muscle results in long-term expression of reporter genes as well as sustained delivery of proteins into the serum. Because this method is potentially applicable clinically, we constructed an AAV vector in which the expression of the mouse erythropoietin (Epo) cDNA is modulated in response to doxycycline. The vector was injected intramuscularly in normal mice. We observed that hematocrit and serum Epo concentrations could be modulated over a 29-week period in response to the presence or absence of doxycycline in the drinking water of these animals. Thus, a regulated gene expression cassette can be incorporated into a single AAV vector, such that intramuscular injection of the vector allows sustained and regulated expression of a desired gene.

Animals↗
PubMed1998

Stable alteration of pre-mRNA splicing patterns by modified U7 small nuclear RNAs.

In several forms of beta-thalassemia, mutations in the second intron of the beta-globin gene create aberrant 5' splice sites and activate a common cryptic 3' splice site upstream. As a result, the thalassemic beta-globin pre-mRNAs are spliced almost exclusively via the aberrant splice sites leading to a deficiency of correctly spliced beta-globin mRNA and, consequently, beta-globin. We have designed a series of vectors that express modified U7 snRNAs containing sequences antisense to either the aberrant 5' or 3' splice sites in the IVS2-705 thalassemic pre-mRNA. Transient expression of modified U7 snRNAs in a HeLa cell line stably expressing the IVS2-705 beta-globin gene restored up to 65% of correct splicing in a sequence-specific and dose-dependent manner. Cell lines that stably coexpressed IVS2-705 pre-mRNA and appropriately modified U7 snRNA exhibited up to 55% of permanent restoration of correct splicing and expression of full-length beta-globin protein. This novel approach provides a potential alternative to gene replacement therapies.

Base Sequence↗
PubMed2005

Sustained transgene expression in rat kidney with naked plasmid DNA and PCR-amplified DNA fragments.

Recently, we developed a kidney-targeted gene transfer technique, in which naked DNA was injected into the renal vein while the renal vein and artery were clamped. Kidney-targeted DNA transfer with only the renal vein clamped is an important modification that may permit less invasive catheter-based gene transfer in future clinical applications. The preparation of PCR-amplified DNA fragments is less time-consuming than that of naked plasmid DNA. We examined rat erythropoietin (Epo) plasmid, pCAGGS-Epo, or PCR-amplified DNA fragment, fCAGGS-Epo, transfer into the rat kidney with only the renal vein clamped. The Epo level peaked at week 3 and then was sustained for 24 weeks, which resulted in significant erythropoiesis. This modified technique, allowing long-term expression of both PCR-amplified DNA fragments and naked plasmid DNA, could potentially be used for catheter-based gene transfer in humans, and could help determine the physiological functions of putative genes.

Animals↗
PubMed2005

Clinical translation of epigenetics in cancer: eN-CORe--a report on the second workshop.

Recent advances in understanding the role that epigenetics plays in cancer pathogenesis and understanding the mechanisms through which these processes regulate gene expression have stimulated considerable interest in developing clinically viable antineoplastic agents that target enzymatic components of transcriptional regulatory complexes responsible for the establishment of pathologic epigenetic modifications that lead to deregulated gene expression in cancer. In January 2003, a workshop was held in Baltimore to discuss the therapeutic potential of several agents that can modify chromatin structure. A follow-up meeting on "Clinical Translation of Epigenetics in Cancer" was held in Charleston, SC, in January 2005. The aim of this workshop was to assess the progress that has been made over the past 2 years in bringing effective therapeutic protocols that use agents capable of reverting pathologic epigenetic changes into the clinic. The meeting was attended by approximately 70 investigators and included formal presentations, panel group discussions, and two break-out sessions that addressed targeted therapies in hematologic and solid tumors. The aim of this article is to summarize topics discussed at this workshop and highlight conclusions as to the immediate and long-term future of epigenetic therapy in cancer.

Animals↗
PubMed2005

Methodological scheme for designing the monitoring of genetically modified crops at the regional scale.

According to EC regulations the deliberate release of genetically modified (GM) crops into the agro-environment needs to be accompanied by environmental monitoring to detect potential adverse effects, e.g. unacceptable levels of gene flow from GM to non-GM crops, or adverse effects on single species or species groups thus reducing biodiversity. There is, however, considerable scientific and public debate on how GM crops should be monitored with sufficient accuracy, discussing questions of potential adverse effects, agro-environmental variables or indicators to be monitored and respective detection methods; Another basic component, the appropriate number and location of monitoring sites, is hardly considered. Currently, no consistent GM crop monitoring approach combines these components systematically. This study focuses on and integrates spatial agro-environmental aspects at a landscape level in order to design monitoring networks. Based on examples of environmental variables associated with the cropping of Bt-Maize (Zea maize L.), herbicide-tolerant (HT) winter oilseed rape (Brassica napus L.), HT sugar beet (Beta vulgaris L.), and starch-modified potato (Solanum tuberosum L.), we develop a transferable framework and assessment scheme that comprises anticipated adverse environmental effects, variables to be measured and monitoring methods. These we integrate with a rule-based GIS (geographic information system) analysis, applying widely available spatial area and point information from existing environmental networks. This is used to develop scenarios with optimised regional GM crop monitoring networks.

Beta vulgaris↗
PubMed2005

Sulfotransferase 1A1 genotype as a potential modifier of breast cancer risk among premenopausal women.

SULT1A1 is involved in biotransformation of many endogenous and exogenous substrates, such as drugs, hormones and tobacco smoke carcinogens. A polymorphism in the sulfotransferase 1A1 gene (SULT1A1) results in an amino acid change from Arg to His at codon 213. The His allele (SULT1A1*2) has been shown to encode a protein with much lower catalytic activity than the protein encoded by the Arg allele (SULT1A1*1). We examined whether this polymorphism modified breast cancer risk in a Finnish-Caucasian study population consisting of 483 breast cancer patients and 482 healthy population controls. No significant genotype effects were seen in the overall breast cancer risk. However, a decreased risk of breast cancer was found among premenopausal women with at least three pregnancies and at least one SULT1A1*2 allele (odds ratio = 0.23, 95% confidence interval = 0.09-0.63) compared to women with two SULT1A1*1 alleles. Our results suggest that the SULT1A1 genotype is not an important risk factor for breast cancer in general, but may modify the risk among premenopausaul women with high parity.

Adolescent↗
PubMed1997

Cellular and molecular neurosurgery: pathways from concept to reality--part I: target disorders and concept approaches to gene therapy of the central nervous system.

Recent advances in cellular and molecular biology and better understanding of genetic and biochemical bases of different central nervous system (CNS) disorders have made gene therapy of the CNS a realistic goal. Concept approaches for gene therapy of CNS disorders are reviewed and include the following: 1) gene replacement with a single normal allele to correct the inherited global neurodegenerative disorders, such as enzyme deficiencies; 2) brain repair to restore the function of a particular subset of cells that were lost because of a neurodegenerative process; 3) gene therapy of brain tumors; and 4) gene therapy of stroke. Techniques of viral vector-mediated CNS transfer of a therapeutic gene, transplantation of genetically modified cells, fetal embryonic implantation and/or implantation of genetically engineered neural progenitor cells, and production of a specific enzyme, neurotransmitter, and/or growth factor are discussed with respect to the therapeutic potential for global and localized CNS neurodegenerative disorders and stroke. Transfection of the CNS tumor cells with the drug susceptibility ("suicide") gene and/or "toxic" gene and antisense strategies and a concept of adoptive immunotherapy of brain tumors are also discussed. Other approaches, such as transfer of drug-resistant genes and monoclonal antibody gene transfer, are briefly discussed. In addition to summarizing current principles of gene therapy for several groups of CNS disorders, the issues that remain to be resolved in clinical reality, such as delivery of the genetic material and regulation of the cellular expression of the transgene, and the negatives associated with the concepts of gene therapy, such as transient gene expression, toxicity of viral proteins, drawbacks of antisense therapy, and the problem of immune response to the transfected protein, have been also identified.

Animals↗
PubMed2002

Nonhuman primate transgenesis: progress and prospects.

The nonhuman primate is used extensively in biomedical research owing to its close similarities to human physiology and human disease pathophysiology. Recently, several groups have initiated efforts to genetically manipulate nonhuman primates to address complex questions concerning primate-specific development and physiological adaptation. Primates pose unique challenges to transgenesis and, although this field is still in its infancy, the potential for obtaining new insights into primate physiology and gene function is unprecedented. This review focuses on the methods and potential applications of genetically altered nonhuman primates in biomedical research.

Adaptation, Physiological↗
PubMed2003

SUMO modification of a novel MAR-binding protein, SATB2, modulates immunoglobulin mu gene expression.

Nuclear matrix attachment regions (MARs) are regulatory DNA sequences that are important for higher-order chromatin organization, long-range enhancer function, and extension of chromatin modifications. Here we characterize a novel cell type-specific MAR-binding protein, SATB2, which binds to the MARs of the endogenous immunoglobulin micro locus in pre-B cells and enhances gene expression. We found that SATB2 differs from the closely related thymocyte-specific protein SATB1 by modifications of two lysines with the small ubiquitive related modifier (SUMO), which are augmented specifically by the SUMO E3 ligase PIAS1. Mutations of the SUMO conjugation sites of SATB2 enhance its activation potential and association with endogenous MARs in vivo, whereas N-terminal fusions with SUMO1 or SUMO3 decrease SATB2-mediated gene activation. Sumoylation is also involved in targeting SATB2 to the nuclear periphery, raising the possibility that this reversible modification of a MAR-binding protein may contribute to the modulation of subnuclear DNA localization.

B-Lymphocytes↗
PubMed1998

Transgenic approaches to the increase of disease resistance in farm animals.

Molecular genetics and reproductive biology techniques enable the transfer of foreign DNA into mammals. Novel approaches to modify disease resistance or susceptibility in livestock are justified by economic and animal welfare concerns. Current research on the improvement of disease resistance by gene transfer focuses on three main strategies, as follows: a) somatic gene transfer, i.e., nucleic acid vaccines b) deletive germ-line gene transfer, i.e., gene knockout c) additive germ-line gene transfer. These strategies aim at either the transient or stable expression of components known to influence non-specific or specific host defence mechanisms, or the disruption of genes known to cause susceptibility to disease. Referring to the source of the effective agent and the site and mode of action, the strategies are termed 'genetic', 'congenital', 'intracellular' and 'extracellular' immunisation. Each gene transfer experiment has to be evaluated carefully with respect to the potential to create novel cases of pathogen resistance or to lose species barriers or cell-type restrictions.

Animals↗
PubMed1995

The therapeutic potential of antisense oligonucleotides.

Specific inhibition of gene expression by antisense agents provides the basis for rational drug discovery based on molecular targets. Due to the specificity of Watson-Crick base-pair hybridization, antisense oligodeoxynucleotides have been used extensively in attempts to inhibit gene expression in both in vitro and in vivo models. Analogues modified from normal phosphodiester oligodeoxynucleotides have entered clinical trials against diseases including AIDS and cancer. Although the precise mechanism of action of these drugs has not been clarified, these oligodeoxynucleotides offer considerable promise as novel molecular therapeutics. We review the recent attempts to harness the therapeutic potential of these oligodeoxynucleotides and appraise the near-term prospects for antisense technology.

Acquired Immunodeficiency Syndrome↗