Long-term expression of glial cell line-derived neurotrophic factor slows, but does not stop retinal degeneration in a model of retinitis pigmentosa.
Long-term expression of glial cell line-derived neurotrophic factor slows, but does not stop retinal degeneration in a model of retinitis pigmentosa.
复制标题
DOI：
10.1111/j.1471-4159.2012.07842.x
复制
发表时间：
2012-09
影响因子：
4.7
通讯作者：
Campochiaro PA
中科院分区：
文献类型：
--
作者：
Ohnaka M;Miki K;Gong YY;Stevens R;Iwase T;Hackett SF;Campochiaro PA
色素性视网膜炎是一组由数百种突变之一引起视杆细胞死亡，视锥细胞逐渐因氧化损伤而死亡的疾病。由于不同的突变通过不同的机制导致杆细胞死亡，因此需要针对突变的治疗。另一种方法是使用神经营养因子来促进光受体的存活，而不管细胞死亡的机制如何，先前的研究已经证明了神经胶质细胞系来源的神经营养因子（GDNF）基因转移的短期效果令人鼓舞。我们在光感受器（Tet/IRBP/GDNF-rd10小鼠）或视网膜色素上皮细胞（Tet/VMD2/GDNF-rd10小鼠）中产生了多环素诱导的GDNF表达的rd10小鼠。在多西环素处理的Tet/IRBP/ Gdnf -rd10小鼠中，Gdnf mRNA在P35时增加9.3 × 104倍，虽然随着时间的推移减少，但在P70时仍增加9.4 × 103倍。在多西环素处理的Tet/VMD2/GDMF-rd10小鼠中，Gdnf mRNA在P35时增加4.5 × 102倍，在P70时无显著降低。在Tet/IRBP/GDNF-rd10小鼠中，GDNF蛋白水平在P35时增加约2.3倍，在P70时增加30%，在Tet/VMD2/GDNF-rd10小鼠中，GDNF蛋白水平在P35时增加30%，在P70时不显著增加。尽管表达不同，Tet/IRBP/GDNF-rd10和Tet/ VMD2/GDNF-rd10小鼠的外核层厚度和平均光性和暗性ERG b波振幅在P35时与rd10小鼠相比均有相当显著的增加，但在P70时仍然显著降低。与rd10小鼠相比，Tet/IRBP/GDNF-rd10和Tet/ VMD2/GDNF-rd10小鼠在P50时锥体密度有相当显著的改善，但在P70时仍然显著。这些数据表明，尽管GDNF的表达存在较大差异，Tet/IRBP/GDNF-rd10和Tet/VMD2/GDNF-rd10对光感受器变性具有相当的减缓作用，但不能阻止其变性。
Retinitis pigmentosa is a group of diseases in which one of hundreds of mutations causes death of rod photoreceptor cells and then cones gradually die from oxidative damage. As different mutations cause rod cell death by different mechanisms, mutation-specific treatments are needed. Another approach is to use a neurotrophic factor to promote photoreceptor survival regardless of the mechanism of cell death, and previous studies have demonstrated encouraging short-term results with gene transfer of glial cell line-derived neurotrophic factor (GDNF). We generated rd10 mice with doxycycline-inducible expression of GDNF in photoreceptors (Tet/IRBP/GDNF-rd10 mice) or retinal pigmented epithelial cells (Tet/VMD2/GDNF-rd10 mice). In doxycycline-treated Tet/IRBP/GDNF-rd10 mice, there was a 9.3 × 104-fold increase in Gdnf mRNA at P35 and although it decreased over time, it was still increased by 9.4 × 103-fold at P70. Gdnf mRNA was increased 4.5 × 102-fold in doxycycline-treated Tet/VMD2/GDMF-rd10 mice at P35 and was not significantly decreased at P70. GDNF protein levels were increased about 2.3-fold at P35 and 30% at P70 in Tet/IRBP/GDNF-rd10 mice, and in Tet/VMD2/GDNF-rd10 mice they were increased 30% at P35 and not significantly increased at P70. Despite the difference in expression, Tet/IRBP/GDNF-rd10 and Tet/ VMD2/GDNF-rd10 mice had comparable significant increases in outer nuclear layer thickness and mean photopic and scotopic ERG b-wave amplitudes compared with rd10 mice at P35 which decreased, but was still significant at P70. Compared with rd10 mice, Tet/IRBP/GDNF-rd10 and Tet/ VMD2/GDNF-rd10 mice had comparable significant improvements in cone density at P50 that decreased, but were still significant at P70. These data indicate that despite a large difference in expression of GDNF, Tet/IRBP/GDNF-rd10 and Tet/VMD2/GDNF-rd10 provide comparable slowing of photoreceptor degeneration, but cannot stop the degeneration.
登录
查看更多内容
影响因子：
5.6
作者：
Komeima, Keiichi;Rogers, Brian S.;Campochiaro, Peter A.
通讯作者：
Campochiaro, Peter A.
影响因子：
5.1
作者：
Nambu, H;Nambu, R;Campochiaro, PA
通讯作者：
Campochiaro, PA
影响因子：
6.2
作者：
Del Rio, Patricia;Irmler, Martin;Ueffing, Marius
通讯作者：
Ueffing, Marius
影响因子：
12.4
作者：
Dalkara, Deniz;Kolstad, Kathleen D.;Flannery, John G.
通讯作者：
Flannery, John G.
影响因子：
4.7
作者：
Dong, Aling;Shen, JiKui;Campochiaro, Peter A.
通讯作者：
Campochiaro, Peter A.