公开(公告)号：US07208467B2

公开(公告)日：2007-04-24

申请号：US10164863

申请日：2002-06-07

申请人： Monty Krieger ,  Helena E. Miettinen

发明人： Monty Krieger ,  Helena E. Miettinen

IPC分类号： A01N37/18 ,  A01N43/16 ,  A01N43/08 ,  A01N31/00 ,  A61K38/00

CPC分类号： A61K31/375 ,  A61K31/00 ,  A61K31/095 ,  A61K31/355 ,  A61K31/365 ,  A61K2300/00

摘要： SR-BI is present at relatively high levels on the membranes of hepatocytes and steroidogenic tissues, including the adrenal gland, testes, and ovaries, where it mediates the uptake and transport of cholesteryl ester from high density lipoproteins. It has been demonstrated that transgenic animals which do not produce SR-BI are healthy, with the exception that the females are infertile. SR-BI KO females have abnormal HDLs, ovulate dysfunctional oocytes and are infertile. Surgical, genetic and pharmacologic methods were used to show that the fertility of SR-BI KO females (or their transplanted oocytes) can be restored in the absence of ovarian and/or extraovarian SR-BI expression by manipulations that modify the structure, composition and/or abundance of their abnormal plasma lipoproteins. These manipulations included inactivation of the apolipoprotein A-I gene and administration of the cholesterol-lowering drug PROBUCOL™. In the absence of treatment, female animals which do not express SR-BI have dramatically reduced levels of offspring, even though they are otherwise healthy and the males normal. Studies demonstrate that they do not produce viable eggs and have a defect involving implantation of normal eggs.

摘要翻译： SR-BI以相当高的水平存在于肝细胞和类固醇生成组织的膜上，包括肾上腺，睾丸和卵巢，其中介导胆固醇酯从高密度脂蛋白的摄取和转运。 已经证明，不产生SR-BI的转基因动物是健康的，除了女性是不育的。 SR-BI KO女性HDL异常，排卵功能异常卵母细胞不育。 使用外科学，遗传学和药理学方法表明，SR-BI KO女性（或其移植的卵母细胞）的生育力可以通过改变结构，组成和功能的操作在没有卵巢和/或外源SR-BI表达的情况下恢复 /或其异常血浆脂蛋白的丰度。 这些操作包括载脂蛋白A-1基因的失活和胆固醇降低药物PROBUCOL TM的给药。 在没有治疗的情况下，不表达SR-BI的雌性动物大大降低了后代的水平，即使它们健康，而雄性也正常。 研究表明，它们不产生活的卵，并且涉及植入正常卵的缺陷。

公开(公告)号：US07361684B2

公开(公告)日：2008-04-22

申请号：US10147651

申请日：2002-05-16

申请人： Monty Krieger ,  Anne Braun ,  Helena E. Miettinen

发明人： Monty Krieger ,  Anne Braun ,  Helena E. Miettinen

IPC分类号： A01N43/16 ,  A61K31/355

CPC分类号： A01K67/0276 ,  A01K2217/075 ,  A01K2227/105 ,  A01K2267/03 ,  A01K2267/0375 ,  A61K31/10 ,  A61K31/34 ,  A61K31/35 ,  A61K49/0008 ,  C07K14/705 ,  C07K14/775 ,  C12N15/8509 ,  Y10S514/824

摘要： Transgenic animals that do not express functional SR-BI and ApoE develop severe atherosclerosis, by age four weeks in transgenic mice. Moreover, these animals exhibit progressive heart dysfunction by as early as age four weeks, and die by age nine weeks. This animal model has now been demonstrated to be useful as a screen for compounds which alleviate the symptoms of atherosclerosis and heart disease. Animals (Apo E−/− SR-BI+/−) were fed PROBUCOL beginning at the time of mating. Offspring are weaned at three weeks and fed PROBUCOL. In contrast to animals (Apo E−/− SR-BI−/−) not fed PROBUCOL, 50% of whom are dead at six weeks, all animals (Apo E−/− SR-BI−/−) on PROBUCOL have a normal phenotype (MRI of heart function, ECG, echocardiogram, histology) at six weeks. At seven to eight months, there is evidence of atherosclerosis and some myocardial infarction. This demonstrates that the compound has a preventative action. Animals who are taken off of the PROBUCOL all die within ten to twelve weeks. In another study, the majority of animals whose parents were not fed PROBUCOL, but who received the PROBUCOL beginning at about five weeks of age, survived for a few months, demonstrating that the compound also has a therapeutic benefit.

摘要翻译： 不表达功能性SR-BI和ApoE的转基因动物在转基因小鼠中4周龄时出现严重的动脉粥样硬化。 此外，这些动物早在四周就显示进行性心脏功能障碍，并且死亡九周。 这种动物模型已被证明可用作减轻动脉粥样硬化和心脏病症状的化合物的筛选。 动物（Apo E - / - SR-BI +/-）在交配时开始给予PROBUCOL。 后代在三周内断奶并喂养PROBUCOL。 与未动用PROBUCOL的动物（Apo E - / - SR-BI - / - ）相比，其中50％在六周内死亡，PROBUCOL上的所有动物（Apo E - / - SR-BI - / - ）都有 正常表型（心脏功能的MRI，ECG，超声心动图，组织学）六周。 七至八个月，有动脉粥样硬化和一些心肌梗死的证据。 这表明该化合物具有预防作用。 从PROBUCOL起飞的动物都会在十到十二个星期内死亡。 在另一项研究中，大多数父母没有喂养PROBUCOL但是在大约五周龄开始接受PROBUCOL的动物存活了几个月，表明该化合物也具有治疗益处。