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    • 4. 发明授权
    • Receptor-deficient mice and cell lines derived therefrom, and uses thereof
    • 受体缺陷小鼠和由其衍生的细胞系及其用途
    • US06278040B1
    • 2001-08-21
    • US08802468
    • 1997-02-19
    • Henry M. SucovRonald M. EvansKenneth R. Chien
    • Henry M. SucovRonald M. EvansKenneth R. Chien
    • C12N1509
    • C12N15/8509A01K67/0276A01K2217/075A01K2227/105A01K2267/03A01K2267/0375A61K31/203A61K49/0008
    • In accordance with the present invention, there are provided targeted loss of function mutant mice which express less than endogenous levels of at least one member of the steroid/thyroid superfamily of receptors in at least one specific tissue type. For example, mutations in the RXR&agr; gene in mouse germlines are lethal in the embryonic stage between E13.5 and E16.5 when bred to homozygosity. The major defect responsible for this lethal effect is hypoplastic development of the ventricular chambers of the heart, which is manifest as a grossly thinned ventricular wall with concurrent defects in ventricular septation. This phenotype is identical to a subset of the effects of embryonic vitamin A deficiency, and therefore establishes RXR&agr; as a genetic component of the vitamin A signaling pathway in cardiac morphogenesis. The cardiac outflow tracts and associated vessels, which are populated by derivatives of the neural crest and which are also sensitive to vitamin A deficiency, are normal in homozygous embryos, indicating the genetic independence of ventricular chamber development. Hepatic differentiation was dramatically but transiently retarded, yet is histologically and morphologically normal. These results ascribe an essential function for the RXR&agr; gene in embryonic development, and provide the first evidence of a requirement for RXR in one of its predicted hormone response pathways.
    • 根据本发明,提供了在至少一种特定组织类型中表达低于受体的类固醇/甲状腺超家族的至少一种成员的内源水平的功能突变小鼠的靶向丧失。 例如,当培育成纯合子时,E13.5和E16.5之间的胚胎阶段,小鼠种系中RXRalpha基因的突变是致命的。 负责这种致死作用的主要缺陷是心脏心室的发育不良,这表现为心室隔膜同时缺陷的严重变薄的心室壁。 这种表型与胚胎维生素A缺乏症的一个亚组相同,因此在心脏形态发生中建立了RXRalpha作为维生素A信号通路的遗传成分。 由神经嵴的衍生物填充并且对维生素A缺乏敏感的心脏流出道和相关血管在纯合胚中是正常的,表明心室发育的遗传独立性。 肝分化显着但短暂延迟,但组织学和形态学正常。 这些结果归因于胚胎发育中RXRalpha基因的基本功能,并提供了其预测的激素反应途径之一的RXR要求的第一个证据。
    • 7. 发明申请
    • Methods of Identifying Functional Characteristics of Promoters, Transcription Modifying Proteins and Transcription Modulating Agents
    • 鉴定启动子,转录修饰蛋白和转录调节剂功能特征的方法
    • US20110263454A1
    • 2011-10-27
    • US13061500
    • 2009-08-28
    • Johan W. JonkerMichael DownesRonald M. Evans
    • Johan W. JonkerMichael DownesRonald M. Evans
    • C40B30/06C40B60/12
    • C12Q1/6897C12N15/1086
    • Provided herein is, inter alia, methods and compositions useful in therapeutic interrogation of complex physiologic pathways by massively parallel and permissive transcriptional screening. Thus, methods and compositions are provided herein that are useful for high-throughput functional analysis of complex, transcriptionally regulated physiological pathways. While examples are provided relating to nuclear receptors, the methods and composition can be generalized and applied to any class of transcription factor or any class of gene product that can regulate the activity of transcription. For example, in addition to nuclear receptors, the methods and compositions provided herein are generally applicable to all known transcription factors and any gene encoded product that modulates said transcription factor activity. Moreover, data obtained through the methods provided herein are directly comparable thereby facilitating high-throughput functional analysis.
    • 本文提供了通过大规模平行和允许的转录筛选在治疗性询问复杂生理学途径中有用的方法和组合物。 因此,本文提供了可用于复杂的转录调节生理学途径的高通量功能分析的方法和组合物。 虽然提供了与核受体相关的实例,但是该方法和组成可以被推广并应用于可以调节转录活性的任何类型的转录因子或任何类型的基因产物。 例如,除了核受体之外,本文提供的方法和组合物通常可应用于调节所述转录因子活性的所有已知转录因子和任何基因编码产物。 此外,通过本文提供的方法获得的数据是直接可比的,因此有助于高通量功能分析。
    • 9. 发明授权
    • Structure of the farnesoid X receptor ligand binding domain and methods of use therefor
    • 法呢酯X受体配体结合域的结构及其用途
    • US07647217B2
    • 2010-01-12
    • US10535042
    • 2003-11-14
    • Michael R DownesMark A. VerdiciaJoseph P. NoelRonald M. EvansLindsey J. BowmanMarianne Bowman
    • Michael R DownesMark A. VerdiciaJoseph P. NoelRonald M. EvansLindsey J. BowmanMarianne Bowman
    • G06G7/58C07K14/00
    • C07K14/70567C07K2299/00G01N33/743G01N2500/00G06F19/16G06F19/706
    • The present invention provides compositions comprising the ligand binding domain (LBD) of a farnesoid X receptor (FXR) in crystalline form. In alternative embodiments, the LBD of FXR is complexed with a ligand therefor. There are provided high resolution structures of FXR complexed with a novel high affinity agonist, fexaramine. The discovered structure of a FXR LBD provides the first three-dimensional view of the structural basis for FXR ligand binding. The present invention further provides a computer for producing a three-dimensional representation of FXR or a complex thereof, and a computer for determining at least a portion of the structure coordinates of FXR or a complex thereof. The present invention further provides methods of using this structural information to predict molecules capable of binding to FXR; to identify compounds with agonist, antagonist or partial agonist activity for FXR; and to determine whether a test compound is capable of binding to the LBD of FXR. The present invention further provides compositions comprising compounds identified by such invention methods.
    • 本发明提供了包含结晶形式的法呢甾X受体(FXR)的配体结合结构域(LBD)的组合物。 在替代实施方案中,FXR的LBD与其配体复合。 提供了与新型高亲和力激动剂fexaramine复合的FXR的高分辨率结构。 所发现的FXR LBD的结构提供了FXR配体结合的结构基础的第一个三维视图。 本发明还提供一种用于产生FXR或其复数的三维表示的计算机,以及用于确定FXR的结构坐标的至少一部分或其复合体的计算机。 本发明还提供使用该结构信息来预测能够结合FXR的分子的方法; 识别FXR激动剂,拮抗剂或部分激动剂活性的化合物; 并确定测试化合物是否能够结合FXR的LBD。 本发明还提供包含通过本发明方法鉴定的化合物的组合物。