共查询到20条相似文献,搜索用时 15 毫秒
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Maeda A Golczak M Chen Y Okano K Kohno H Shiose S Ishikawa K Harte W Palczewska G Maeda T Palczewski K 《Nature chemical biology》2012,8(2):170-178
Vertebrate vision is initiated by photoisomerization of the visual pigment chromophore 11-cis-retinal and is maintained by continuous regeneration of this retinoid through a series of reactions termed the retinoid cycle. However, toxic side reaction products, especially those involving reactive aldehyde groups of the photoisomerized product, all-trans-retinal, can cause severe retinal pathology. Here we lowered peak concentrations of free all-trans-retinal with primary amine-containing Food and Drug Administration (FDA)-approved drugs that did not inhibit chromophore regeneration in mouse models of retinal degeneration. Schiff base adducts between all-trans-retinal and these amines were identified by MS. Adducts were observed in mouse eyes only when an experimental drug protected the retina from degeneration in both short-term and long-term treatment experiments. This study demonstrates a molecular basis of all-trans-retinal-induced retinal pathology and identifies an assemblage of FDA-approved compounds with protective effects against this pathology in a mouse model that shows features of Stargardt's disease and age-related retinal degeneration. 相似文献
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Shobi Veleri Csilla H. Lazar Bo Chang Paul A. Sieving Eyal Banin Anand Swaroop 《Disease models & mechanisms》2015,8(2):109-129
Retinal neurodegeneration associated with the dysfunction or death of photoreceptors is a major cause of incurable vision loss. Tremendous progress has been made over the last two decades in discovering genes and genetic defects that lead to retinal diseases. The primary focus has now shifted to uncovering disease mechanisms and designing treatment strategies, especially inspired by the successful application of gene therapy in some forms of congenital blindness in humans. Both spontaneous and laboratory-generated mouse mutants have been valuable for providing fundamental insights into normal retinal development and for deciphering disease pathology. Here, we provide a review of mouse models of human retinal degeneration, with a primary focus on diseases affecting photoreceptor function. We also describe models associated with retinal pigment epithelium dysfunction or synaptic abnormalities. Furthermore, we highlight the crucial role of mouse models in elucidating retinal and photoreceptor biology in health and disease, and in the assessment of novel therapeutic modalities, including gene- and stem-cell-based therapies, for retinal degenerative diseases.KEY WORDS: Mouse mutants, Photoreceptor, Retinal development, Retinal disease 相似文献
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Pathways to motor neuron degeneration in transgenic mouse models 总被引:5,自引:0,他引:5
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurological disorder characterized by the selective loss of motor neurons. A pathological hallmark of both sporadic and familial ALS is the presence of abnormal accumulations of neurofilament and peripherin proteins in motor neurons. In the past decade, transgenic mouse approaches have been used to address the role of such cytoskeletal abnormalities in motor neuron disease and also to unravel the pathogenesis caused by mutations in the gene coding for superoxide dismutase 1 (SOD1) that account for ~20% of familial ALS cases. In mouse models, disparate effects could result from different types of intermediate filament (IF) aggregates. Perikaryal IF accumulations induced by the overexpression of any of the three wild-type neurofilament proteins were quite well tolerated by motor neurons. Indeed, perikaryal swellings provoked by NF-H overexpression can even confer protection against toxicity of mutant SOD1. Other types of IF aggregates seem neurotoxic, such as those found in transgenic mice overexpressing either peripherin or an assembly-disrupting NF-L mutant. Moreover, understanding the toxicity of SOD1 mutations has been surprisingly difficult. The analysis of transgenic mice expressing mutant SOD1 has yielded complex results, suggesting that multiple pathways may contribute to disease that include the involvement of non-neuronal cells. 相似文献
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Factor VIII (FVIII) is an essential component in blood coagulation, a deficiency of which causes the serious bleeding disorder
hemophilia A. Recently, with the development of purification level and recombinant techniques, protein replacement treatment
to hemophiliacs is relatively safe and can prolong their life expectancy. However, because of the possibility of unknown contaminants
in plasma-derived FVIII and recombinant FVIII, and high cost for hemophiliacs to use these products, gene therapy for hemophilia
A is an attractive alternative to protein replacement therapy. Thus far, the adeno-associated virus (AAV) is a promising vector
for gene therapy. Further improvement of the virus for clinical application depends on better understanding of the molecular
structure and fate of the vector genome. It is likely that hemophilia will be the first genetic disease to be cured by somatic
cell gene therapy. 相似文献
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PARP1 gene knock-out increases resistance to retinal degeneration without affecting retinal function
Sahaboglu A Tanimoto N Kaur J Sancho-Pelluz J Huber G Fahl E Arango-Gonzalez B Zrenner E Ekström P Löwenheim H Seeliger M Paquet-Durand F 《PloS one》2010,5(11):e15495
Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases affecting photoreceptors and causing blindness in humans. Previously, excessive activation of enzymes belonging to the poly-ADP-ribose polymerase (PARP) group was shown to be involved in photoreceptor degeneration in the human homologous rd1 mouse model for RP. Since there are at least 16 different PARP isoforms, we investigated the exact relevance of the predominant isoform - PARP1 - for photoreceptor cell death using PARP1 knock-out (KO) mice. In vivo and ex vivo morphological analysis using optic coherence tomography (OCT) and conventional histology revealed no major alterations of retinal phenotype when compared to wild-type (wt). Likewise, retinal function as assessed by electroretinography (ERG) was normal in PARP1 KO animals. We then used retinal explant cultures derived from wt, rd1, and PARP1 KO animals to test their susceptibility to chemically induced photoreceptor degeneration. Since photoreceptor degeneration in the rd1 retina is triggered by a loss-of-function in phosphodiesterase-6 (PDE6), we used selective PDE6 inhibition to emulate the rd1 situation on non-rd1 genotypes. While wt retina subjected to PDE6 inhibition showed massive photoreceptor degeneration comparable to rd1 retina, in the PARP1 KO situation, cell death was robustly reduced. Together, these findings demonstrate that PARP1 activity is in principle dispensable for normal retinal function, but is of major importance for photoreceptor degeneration under pathological conditions. Moreover, our results suggest that PARP dependent cell death or PARthanatos may play a major role in retinal degeneration and highlight the possibility to use specific PARP inhibitors for the treatment of RP. 相似文献
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Zinc-desferrioxamine attenuates retinal degeneration in the rd10 mouse model of retinitis pigmentosa
Obolensky A Berenshtein E Lederman M Bulvik B Alper-Pinus R Yaul R Deleon E Chowers I Chevion M Banin E 《Free radical biology & medicine》2011,51(8):1482-1491
Iron-associated oxidative injury plays a role in retinal degeneration such as age-related macular degeneration and retinitis pigmentosa. The metallo-complex zinc-desferrioxamine (Zn/DFO) may ameliorate such injury by chelation of labile iron in combination with release of zinc. We explored whether Zn/DFO can affect the course of retinal degeneration in the rd10 mouse model of retinitis pigmentosa. Zn/DFO-treated animals showed significantly higher electroretinographic responses at 3 and 4.5 weeks of age compared with saline-injected controls. Corresponding retinal (photoreceptor) structural rescue was observed by quantitative histological and immunohistochemical techniques. When administered alone, the components of the complex, Zn and DFO, showed a lesser, partial effect. TBARS, a marker of lipid peroxidation, and levels of oxidative DNA damage as quantified by 8-OHdG immunostaining were significantly lower in Zn/DFO-treated retinas compared with saline-injected controls. Reduced levels of retinal ferritin as well as reduced iron content within ferritin molecules were measured in Zn/DFO-treated retinas. The data, taken together, suggest that the protective effects of the Zn/DFO complex are mediated through modulation of iron bioavailability, leading to attenuation of oxidative injury. Reducing iron-associated oxidative stress using complexes such as Zn/DFO may serve as a “common pathway” therapeutic approach to attenuate injury in retinal degeneration. 相似文献
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P Briand 《Journal de génétique humaine》1989,37(4-5):289-297
Somatic gene therapies are based on the introduction of genes in somatic cells in an attempt to correct a gene defect, to induce a resistance or to add a particular activity. In their principle, they are not very different from organ grafts and do not set specific ethic problems. Their application to human therapy has to be subjected to a critical evaluation of their harmlessness and efficiency. For this purpose, animal models of somatic gene therapy are essential. Such therapy have been tried in bone marrow and endothelial cells, in fibroblasts, keratinocytes hepatocytes, but also by direct transfer of genes in the organism. These different approaches are briefly reviewed and compared in this article. 相似文献
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Bu L Yan S Jin M Jin Y Yu C Xiao S Xie Q Hu L Xie Y Solitang Y Liu J Zhao G Kong X 《Genomics》2002,80(1):38-44
We established a recessive cataract model from a spontaneous mutation in the KUNMING outbred mice. Lens opacity appears 11 days after birth. Slit lamp examination reveals that the opacity mainly localizes to the nuclear region of the lens. Histological analysis shows a severe degeneration of the epithelial cells underneath the anterior lens capsule, whereas those cells in the equatorial region display an excessive proliferation and migration. Within the cortical area underneath the posterior lens capsule, both vacuoles and morgagnian-like bodies are seen. Blue-stained spherical bodies are observed in the embryonic nucleus, forming a Y-like pattern. We mapped the disease locus and found a homozygous G to A nucleotide conversion at position 489 of Crygs in mutant mice, leading to a truncated gene product (Trp163Stop). This finding suggests that CRYGS is not only a lens structural protein, but is also likely to be involved in epithelial cell proliferation, apoptosis, and migration. 相似文献
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