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Pey R Bach J Schieren G Gretz N Hafner M 《In vitro cellular & developmental biology. Animal》1999,35(10):571-579
Summary Autosomal dominant polycystic kidney disease (ADPKD) is one of the most frequent human inherited diseases. The main feature
of the disease is the development of renal cysts, first occurring in the proximal tubules, and with time, dominating all segments
of the nephron, leading to end-stage renal disease in 50% of the patients in their fifth decade of life. A therapy for polycystic
kidney disease (PKD) has not yet been developed. Patients coming to end-stage ADPKD require long-term dialysis and/or transplantation.
A suitable animal model to study ADPKD is the spontaneously mutated Han:SPRD (cy/ +) rat, but a method to cultivate Han:SPRD (cy/ +) derived renal cells which preserves their ability to form cyst-like structures in vitro has previously not been reported.
Based on this well-characterized animal model, we developed a cell culture model of renal cyst formation in vitro. When renal
cells of the Han:SPRD (cy/ +) rat were isolated and cultured under conditions that prevent cell-substratum adhesion, large amounts of cyst-like structures
were formed de novo from Han:SPRD (cy/ +) derived renal cells, but only a few from control rat renal cells. In contrast, when cultivated on plastic as monolayer
cultures, Han:SPRD (cy/ +)-derived and control rat-derived renal cells were indistinguishable and did not form cyst-like structures. Immunohistochemical
characterization of the cyst-like structures suggests tubular epithelial origin of the cyst-forming cells. The amount of cysts
formed from Han:SPRD (cy/ +)-derived renal cells grown in a stationary suspension culture is susceptible to modulation by different conditions. Human
cyst fluid and epidermal growth factor both stimulated the formation of cysts from Han:SPRD (cy/ +)-derived renal cells whereas taxol inhibited cystogenesis. In contrast, neither human cyst fluid nor epidermal growth
factor affected the amount of cysts formed by control rat renal cells. As the culture model reported here allows not only
the distinction of PKD-derived tubular epithelium from its normal counterpart, but also the modulation of cyst formation especially
by Han:SPRD (cy/ +)-derived renal cells, it might be a useful prescreening protocol for potential treatments for PKD and thus reduce the
need for animal experiments.
Both authors contributed equally to the work. 相似文献
54.
Zhou HM Weskamp G Chesneau V Sahin U Vortkamp A Horiuchi K Chiusaroli R Hahn R Wilkes D Fisher P Baron R Manova K Basson CT Hempstead B Blobel CP 《Molecular and cellular biology》2004,24(1):96-104
Congenital heart disease is the most common form of human birth defects, yet much remains to be learned about its underlying causes. Here we report that mice lacking functional ADAM19 (mnemonic for a disintegrin and metalloprotease 19) exhibit severe defects in cardiac morphogenesis, including a ventricular septal defect (VSD), abnormal formation of the aortic and pulmonic valves, leading to valvular stenosis, and abnormalities of the cardiac vasculature. During mouse development, ADAM19 is highly expressed in the conotruncus and the endocardial cushion, structures that give rise to the affected heart valves and the membranous ventricular septum. ADAM19 is also highly expressed in osteoblast-like cells in the bone, yet it does not appear to be essential for bone growth and skeletal development. Most adam19(-/-) animals die perinatally, likely as a result of their cardiac defects. These findings raise the possibility that mutations in ADAM19 may contribute to human congenital heart valve and septal defects. 相似文献
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56.
Tubio G Nerli B Picó G 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2004,799(2):293-301
In order to develop possible correlations to predict partioning behaviour of proteins, five mammalian albumins (goat, bovine, equine, human and pig ones) with similar physico-chemical properties (molecular mass and isoelectrical point) were chosen. Evaluation of the relationship between hydrophobicity and partitioning coefficient (Kr) in polyethylenglycol-dextran (PEG-DxT500) systems formed by polyethyleneglycols of different molecular mass (3350, 6000 and 10,000) was investigated by estimating relative surface hydrophobicity (So) with a fluorescent probe, 1 anilino-8-naphthalene sulfonate. No relationship between Kr and So was found for systems formed by PEG3350, while aqueous two-phase systems with PEG6000 and PEG10,000 gave better correlations. The results obtained may be explained on the basis of an increase in the interaction between the latter PEGs and the protein due to their higher hydrophobic character which increases as the PEG molecular mass does so. In this way, systems with PEGs of higher molecular mass give the highest resolution to exploit hydrophobicity in partitioning. 相似文献
57.
Vaitaitis GM Poulin M Sanderson RJ Haskins K Wagner DH 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(7):3455-3459
It has been speculated that autoimmune diseases are caused by failure of central tolerance. However, this remains controversial. We have suggested that CD40 expression identifies autoaggressive T cells in the periphery of autoimmune prone mice. In this study, we report that CD40 was cloned from autoaggressive T cells and that engagement induces expression and nuclear translocation of the recombinases, recombination activating gene (RAG) 1 and RAG2 in the autoaggressive, but not in the nonautoaggressive, peripheral T cell population. Furthermore, we demonstrate that CD40 engagement induces altered TCR Valpha, but not Vbeta, expression in these cells. Therefore, CD40-regulated expression of RAG1 and RAG2 in peripheral T cells may constitute a novel pathway for the generation of autoaggressive T cells. 相似文献
58.
Tibbetts AS Oesterlin L Chan SY Kramer G Hardesty B Appling DR 《The Journal of biological chemistry》2003,278(34):31774-31780
Initiation of protein synthesis in mitochondria and chloroplasts is widely believed to require a formylated initiator methionyl-tRNA (fMet-tRNAfMet) in a process involving initiation factor 2 (IF2). However, yeast strains disrupted at the FMT1 locus, encoding mitochondrial methionyl-tRNA formyltransferase, lack detectable fMet-tRNAfMet but exhibit normal mitochondrial function as evidenced by normal growth on non-fermentable carbon sources. Here we show that mitochondrial translation products in Saccharomyces cerevisiae were synthesized in the absence of formylated initiator tRNA. ifm1 mutants, lacking the mitochondrial initiation factor 2 (mIF2), are unable to respire, indicative of defective mitochondrial protein synthesis, but their respiratory defect could be complemented by plasmid-borne copies of either the yeast IFM1 gene or a cDNA encoding bovine mIF2. Moreover, the bovine mIF2 sustained normal respiration in ifm1 fmt1 double mutants. Bovine mIF2 supported the same pattern of mitochondrial translation products as yeast mIF2, and the pattern did not change in cells lacking formylated Met-tRNAfMet. Mutant yeast lacking any mIF2 retained the ability to synthesize low levels of a subset of mitochondrially encoded proteins. The ifm1 null mutant was used to analyze the domain structure of yeast mIF2. Contrary to a previous report, the C terminus of yeast mIF2 is required for its function in vivo, whereas the N-terminal domain could be deleted. Our results indicate that formylation of initiator methionyl-tRNA is not required for mitochondrial protein synthesis. The ability of bovine mIF2 to support mitochondrial translation in the yeast fmt1 mutant suggests that this phenomenon may extend to mammalian mitochondria as well. 相似文献
59.
A mathematical model examined a potential therapy for controlling viral infections using genetically modified viruses. The control of the infection is an indirect effect of the selective elimination by an engineered virus of infected cells that are the source of the pathogens. Therefore, this engineered virus could greatly compensate for a dysfunctional immune system compromised by AIDS. In vitro studies using engineered viruses have been shown to decrease the HIV-1 load about 1000-fold. However, the efficacy of this potential treatment for reducing the viral load in AIDS patients is unknown. The present model studied the interactions among the HIV-1 virus, its main host cell (activated CD4+ T cells), and a therapeutic engineered virus in an in vivo context; and it examined the conditions for controlling the pathogen. This model predicted a significant drop in the HIV-1 load, but the treatment does not eradicate HIV. A basic estimation using a currently engineered virus indicated an HIV-1 load reduction of 92% and a recovery of host cells to 17% of their normal level. Greater success (98% HIV reduction, 44% host cells recovery) is expected as more competent engineered viruses are designed. These results suggest that therapy using viruses could be an alternative to extend the survival of AIDS patients. 相似文献
60.
Garofalo C Trinko R Kramer G Appling DR Hardesty B 《Archives of biochemistry and biophysics》2003,413(2):243-252
Yeast mitochondrial initiation factor 2 (ymIF2) is encoded by the nuclear IFM1 gene. A His-tagged version of ymIF2, lacking its predicted mitochondrial presequence, was expressed in Escherichia coli and purified. Purified ymIF2 bound both E. coli fMet-tRNA(f)(Met) and Met-tRNA(f)(Met), but binding of formylated initiator tRNA was about four times higher than that of the unformylated species under the same conditions. In addition, the isolated ymIF2 was compared to E. coli IF2 in four other assays commonly used to characterize this initiation factor. Formylated and nonformylated Met-tRNA(f)(Met) were bound to E. coli 30S ribosomal subunits in the presence of ymIF2, GTP, and a short synthetic mRNA. The GTPase activity of ymIF2 was found to be dependent on the presence of E. coli ribosomes. The ymIF2 protected fMet-tRNA(f)(Met) to about the same extent as E. coli IF2 against nonenzymatic deaminoacylation. In contrast to E. coli IF2, the complex formed between ymIF2 and fMet-tRNA(f)(Met) was not stable enough to be analyzed in a gel shift assay. In similarity to other IF2 species isolated from bacteria or bovine mitochondria, the N-terminal domain could be eliminated without loss of initiator tRNA binding activity. 相似文献