Fabry M E, Costantini F, Pachnis A, Suzuka S M, Bank N, Aynedjian H S, Factor S M, Nagel R L
Department of Medicine, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461.
Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12155-9. doi: 10.1073/pnas.89.24.12155.
A line of transgenic mice with two cointegrated transgenes, the human beta S- and alpha 2-globin genes, linked to the beta-globin locus control region was produced and bred with mice carrying a deletion of the mouse beta major-globin gene. In transgenic mice homozygous for the beta major deletion (alpha H beta S[beta MDD]; where alpha H is human alpha-globin and MD is mouse deletion), 72.5 +/- 2.4% (mean +/- SD) of the beta-chains are beta S and the ratio of alpha H- to beta S-globin was 0.73. Introduction of a heterozygous mouse alpha-globin deletion into mice homozygous for the beta major deletion (alpha H beta S[alpha MD beta MDD]) resulted in 65.1 +/- 8.5% beta S and a human alpha/beta ratio of 0.89 +/- 0.2. Sickling occurs in 95% of erythrocytes from alpha H beta S[beta MDD] mice after slow deoxygenation. Transmission electron microscopy revealed polymer fiber formation but not fascicles of fiber. Increased organ weight was noted in lung, spleen, and kidney of transgenic mice vs. controls that may be due to hypertrophy or increased blood volume in the lungs and/or increased tissue water content. The hemoglobin content of lung, spleen, and kidney was also elevated in transgenic animals due to trapped hemoglobin and/or increased blood volume. When transgenic and control mice were examined by magnetic resonance imaging at 9.4 tesla, some transgenic animals had enlarged kidneys with prolonged relaxation time, consistent with increased organ weight and water content. The glomerular filtration rate was elevated in transgenic animals, which is characteristic of young sickle cell patients. Furthermore, exposure to hypoxia resulted in significantly decreased hematocrit, increased erythrocyte density, and induced a urine-concentrating defect. We conclude that the transgenic mouse line reported here has chronic organ damage and further hematological and organ dysfunction can be induced by hypoxia.
构建了一系列整合有两个人类转基因（βS -珠蛋白基因和α2 -珠蛋白基因）且与β -珠蛋白基因座控制区相连的转基因小鼠，并将其与携带小鼠β -珠蛋白主要基因缺失的小鼠进行杂交。在β -珠蛋白主要基因缺失的纯合转基因小鼠（αHβS[βMDD]；其中αH为人α -珠蛋白，MD为小鼠缺失）中，72.5±2.4%（平均值±标准差）的β -链为βS，αH -珠蛋白与βS -珠蛋白的比例为0.73。将杂合的小鼠α -珠蛋白缺失引入β -珠蛋白主要基因缺失的纯合小鼠（αHβS[αMDβMDD]）后，βS占65.1±8.5%，人α/β比例为0.89±0.2。缓慢脱氧后，αHβS[βMDD]小鼠95%的红细胞发生镰变。透射电子显微镜显示有聚合物纤维形成，但未发现纤维束。与对照相比，转基因小鼠的肺、脾和肾重量增加，这可能是由于肺肥大或血容量增加和/或组织含水量增加所致。由于血红蛋白滞留和/或血容量增加，转基因动物肺、脾和肾中的血红蛋白含量也升高。当在9.4特斯拉下通过磁共振成像检查转基因小鼠和对照小鼠时，一些转基因动物的肾脏增大，弛豫时间延长，这与器官重量和含水量增加一致。转基因动物的肾小球滤过率升高，这是年轻镰状细胞病患者的特征。此外，暴露于低氧环境会导致血细胞比容显著降低、红细胞密度增加，并引发尿液浓缩功能缺陷。我们得出结论，本文报道的转基因小鼠品系存在慢性器官损伤，低氧可诱发进一步的血液学和器官功能障碍。
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