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41. 发明授权

US07214482B2 Steroid-activated nuclear receptors and uses therefor 有权
标题翻译：类固醇激活的核受体及其用途
公开(公告)号：US07214482B2
公开(公告)日：2007-05-08
申请号：US10081555
申请日：2002-02-20
申请人： Ronald M. Evans , Bruce Blumberg
发明人： Ronald M. Evans , Bruce Blumberg
IPC分类号： C12Q1/68
CPC分类号： A01K67/0275 , A01K2217/05 , A01K2227/105 , A01K2267/03 , A61K38/00 , C07K14/70567 , C07K2319/71 , C12N15/8509 , C12N2830/008 , C12Q1/6897 , G01N33/743 , G01N2333/90245 , G01N2500/00
摘要： A novel nuclear receptor, termed the steroid and xenobiotic receptor (SXR), a broad-specificity sensing receptor that is a novel branch of the nuclear receptor superfamily, has been discovered. SXR forms a heterodimer with RXR that can bind to and induce transcription from response elements present in steroid-inducible cytochrome P450 genes in response to hundreds of natural and synthetic compounds with biological activity, including therapeutic steroids as well as dietary steroids and lipids. Instead of hundreds of receptors, one for each inducing compound, the invention SXR receptors monitor aggregate levels of inducers to trigger production of metabolizing enzymes in a coordinated metabolic pathway. Agonists and antagonists of SXR are administered to subjects to achieve a variety of therapeutic goals dependent upon modulating metabolism of one or more endogenous steroids or xenobiotics to establish homeostasis. An assay is provided for identifying steroid drugs that are likely to cause drug interaction if administered to a subject in therapeutic amounts. Transgenic animals are also provided which express human SXR, thereby serving as useful models for human response to various agents which potentially impact P450-dependent metabolic processes.
摘要翻译：已经发现了一种称为类固醇和异种生物受体（SXR）的新型核受体，作为核受体超家族的新分支的广泛特异性感受器受体。 SXR与RXR形成异源二聚体，其可以结合并诱导存在于类固醇诱导细胞色素P450基因中的响应元件的转录，以响应数百种具有生物活性的天然和合成化合物，包括治疗类固醇以及膳食类固醇和脂质。代替数百个受体，每个诱导化合物一个，本发明SXR受体监测诱导剂的总体水平以引发协同代谢途径中代谢酶的产生。 SXR的激动剂和拮抗剂被施用于受试者以实现依赖于调节一种或多种内源性类固醇或异种生物的代谢以建立体内平衡的各种治疗目标。提供了用于鉴定如果以治疗量施用给受试者的可能引起药物相互作用的类固醇药物的测定。还提供了表达人SXR的转基因动物，从而作为人类对各种可能影响P450依赖性代谢过程的药物的反应的有用模型。

42. 发明授权

US07119077B1 Multimeric forms of members of the steroid/thyroid superfamily of receptors with the ultraspiracle receptor 有权
标题翻译：具有超吸收受体的受体的类固醇/甲状腺超家族成员的多聚体形式
公开(公告)号：US07119077B1
公开(公告)日：2006-10-10
申请号：US09526298
申请日：2000-03-15
申请人： Ronald M. Evans , Michael B. McKeown , Anthony E. Oro , William A. Segraves , Tso-Pang Yao
发明人： Ronald M. Evans , Michael B. McKeown , Anthony E. Oro , William A. Segraves , Tso-Pang Yao
IPC分类号： C07H21/04 , A61K48/00
CPC分类号： C07K14/721
摘要： In accordance with the present invention, it has been discovered that various members of the steroid/thyroid superfamily of receptors can interact with the insect-derived ultraspiracle receptor, to form multimeric species. Accordingly, the interaction of at least one member of the steroid/thyroid superfamily of receptors with at least the dimerization domain of the ultraspiracle receptor modulates the ability of said member of the steroid/thyroid superfamily of receptors to transactivate transcription of genes maintained under hormone expression control in the presence of the cognate ligand for said member of the superfamily.
摘要翻译：根据本发明，已经发现，受体的类固醇/甲状腺超家族的各种成员可以与昆虫来源的超吸虫受体相互作用，形成多聚体物质。因此，至少一种受体的类固醇/甲状腺超家族与至少二尖晶状体受体的二聚化结构域之间的相互作用调节所述类固醇/甲状腺超家族成员能够激活维持在激素表达下的基因转录的能力在所述超家族成员的同源配体存在下控制。

43. 发明授权

US06911537B2 Xenobiotic compound modulated expression systems and uses therefor 有权
标题翻译：异生复合调节表达系统及其用途
公开(公告)号：US06911537B2
公开(公告)日：2005-06-28
申请号：US09840008
申请日：2001-04-20
申请人： Ronald M. Evans
发明人： Ronald M. Evans
IPC分类号： A61K38/00 , C07K14/705 , C07H21/02 , A61K31/70 , C07H21/04 , C12N15/00
CPC分类号： C07K14/70567 , A01K2217/05 , A61K38/00
摘要： A novel nuclear receptor, termed the steroid and xenobiotic receptor (SXR), a broad-specificity sensing receptor that is a novel branch of the nuclear receptor superfamily, has been discovered. SXR forms a heterodimer with RXR that can bind to and induce transcription from response elements present in steroid-inducible cytochrome P450 genes in response to hundreds of natural and synthetic compounds with biological activity, including therapeutic steroids as well as dietary steroids and lipids. Instead of hundreds of receptors, one for each inducing compound, the invention SXR receptors monitor aggregate levels of inducers to trigger production of metabolizing enzymes in a coordinated metabolic pathway. Agonists and antagonists of SXR are administered to subjects to achieve a variety of therapeutic goals dependent upon modulating metabolism of one or more endogenous steroids or xenobiotics to establish homeostasis. An assay is provided for identifying steroid drugs that are likely to cause drug interaction if administered to a subject in therapeutic amounts. Transgenic animals are also provided which express human SXR, thereby serving as useful models for human response to various agents which potentially impact P450-dependent metabolic processes. Also provided are expression systems and expression vectors having SXR receptors and the like operably linked to target genes of interest.
摘要翻译：已经发现了一种称为类固醇和异种生物受体（SXR）的新型核受体，作为核受体超家族的新分支的广泛特异性感受受体。 SXR与RXR形成异源二聚体，其可以结合并诱导存在于类固醇诱导细胞色素P450基因中的响应元件的转录，以响应数百种具有生物活性的天然和合成化合物，包括治疗类固醇以及膳食类固醇和脂质。代替数百个受体，每个诱导化合物一个，本发明SXR受体监测诱导剂的总体水平以引发协同代谢途径中代谢酶的产生。 SXR的激动剂和拮抗剂被施用于受试者以实现依赖于调节一种或多种内源性类固醇或异种生物的代谢以建立体内平衡的各种治疗目标。提供了用于鉴定如果以治疗量施用给受试者的可能引起药物相互作用的类固醇药物的测定。还提供了表达人SXR的转基因动物，从而作为人类对各种可能影响P450依赖性代谢过程的药物的反应的有用模型。还提供了具有可操作地连接到目标靶基因的SXR受体等的表达系统和表达载体。

44. 发明授权

US06809178B2 Steroid-activated nuclear receptors and uses therefor 有权
标题翻译：类固醇激活的核受体及其用途
公开(公告)号：US06809178B2
公开(公告)日：2004-10-26
申请号：US09227718
申请日：1999-01-08
申请人： Ronald M. Evans , Bruce Blumberg
发明人： Ronald M. Evans , Bruce Blumberg
IPC分类号： C07K1400
CPC分类号： C07K14/70567 , A61K38/00
摘要： A novel nuclear receptor, termed the steroid and xenobiotic receptor (SXR), a broad-specificity sensing receptor that is a novel branch of the nuclear receptor superfamily, has been discovered. SXR forms a heterodimer with RXR that can bind to and induce transcription from response elements present in steroid-inducible cytochrome P450 genes in response to hundreds of natural and synthetic compounds with biological activity, including therapeutic steroids as well as dietary steroids and lipids. Instead of hundreds of receptors, one for each inducing compound, the invention SXR receptors monitor aggregate levels of inducers to trigger production of metabolizing enzymes in a coordinated metabolic pathway. Agonists and antagonists of SXR are administered to subjects to achieve a variety of therapeutic goals dependent upon modulating metabolism of one or more endogenous steroids or xenobiotics to establish homeostasis. An assay is provided for identifying steroid drugs that are likely to cause drug interaction if administered to a subject in therapeutic amounts.
摘要翻译：已经发现了一种称为类固醇和异种生物受体（SXR）的新型核受体，作为核受体超家族的新分支的广泛特异性感受器受体。 SXR与RXR形成异源二聚体，其可以结合并诱导存在于类固醇诱导细胞色素P450基因中的响应元件的转录，以响应数百种具有生物活性的天然和合成化合物，包括治疗类固醇以及膳食类固醇和脂质。代替数百个受体，每个诱导化合物一个，本发明SXR受体监测诱导剂的总体水平以引发协同代谢途径中代谢酶的产生。 SXR的激动剂和拮抗剂被施用于受试者以实现依赖于调节一种或多种内源性类固醇或异种生物的代谢以建立体内平衡的各种治疗目标。提供了用于鉴定如果以治疗量施用给受试者的可能引起药物相互作用的类固醇药物的测定。

45. 发明授权

US06756491B2 Steroid-activated nuclear receptors and uses therefor 失效
标题翻译：类固醇激活的核受体及其用途
公开(公告)号：US06756491B2
公开(公告)日：2004-06-29
申请号：US09005286
申请日：1998-01-09
申请人： Ronald M. Evans , Bruce Blumberg
发明人： Ronald M. Evans , Bruce Blumberg
IPC分类号： C12Q170
CPC分类号： C07K14/70567 , A61K38/00
摘要： In accordance with the present invention, there is provided an example of a novel class of nuclear receptor(s), termed the steroid X receptor (SXR). SXR is expressed almost exclusively in the liver, the primary site of xenobiotic and steroid catabolism. Unlike classical steroid receptors, SXR heterodimerizes with RXR and binds to directly repeated sequences related to the half-site, AGTTCA. SXR can activate transcription through response elements found in some steroid inducible P450 genes in response to a wide variety of natural and synthetic steroid hormones, including antagonists such as PCN—ideal properties for a “steroid sensing receptor” which mediates the physiological effect(s) of hormones. SXR represents the first new class of steroid receptors described since the identification of the mineralocorticoid receptor ten years ago. Also provided according to the invention are nucleic acid sequences encoding the above-identified receptors, as well as constructs and cells containing same, and probes derived therefrom. Furthermore, it has also been discovered that a wide variety of substrates modulate the transcription activating effects of invention receptors.
摘要翻译：根据本发明，提供了称为类固醇X受体（SXR）的新型核受体类的实例。 SXR几乎完全表达在肝脏中，是异种生物和类固醇分解代谢的主要部位。与经典类固醇受体不同，SXR与RXR异二聚化，并与直接重复与半位点AGTTCA相关的序列结合。 SXR可通过响应多种天然和合成类固醇激素（包括拮抗剂，例如介导生理作用的“类固醇感受因子”的PCN-理想性质）的一些类固醇诱导型P450基因中发现的应答元件来激活转录，的激素。 SXR代表自十年前鉴定盐皮质激素受体以来描述的第一类新的类固醇受体。根据本发明还提供了编码上述受体的核酸序列，以及包含其的构建体和细胞，以及由其衍生的探针。此外，还发现各种底物调节发明受体的转录激活作用。

46. 发明授权

US06677311B1 Inducible HSV-TK in transformed cell populations 失效
标题翻译：用于选择性抑制完整生物体中组织型或细胞系生长或引起死亡的方法
公开(公告)号：US06677311B1
公开(公告)日：2004-01-13
申请号：US08464271
申请日：1995-06-05
申请人： Ronald M. Evans , Emiliana Borrelli , Richard Alan Heyman
发明人： Ronald M. Evans , Emiliana Borrelli , Richard Alan Heyman
IPC分类号： A01N4304
CPC分类号： A61K48/00
摘要： The present invention discloses a new selective method for inducibly and genetically ablating specific cell lineages in transgenic cell populations, e.g., in transgenic animals. The new method, which permits the production of stable transgenic perigees, and thus can be used at various stages of development of a transgenic cell population, allows both the timing and the degree of cellular ablation to be controlled. As a result the method can be used for a variety of therapeutic applications, as well as to study cell lineages and organogenesis, plus the capacity that residual stem cells have for regeneration.
摘要翻译：本发明公开了一种用于在转基因细胞群体（例如转基因动物）中诱导和遗传地消融特异性细胞谱系的新的选择性方法。允许生产稳定的转基因百叶窗并因此可以在转基因细胞群体的不同发展阶段使用的新方法允许控制细胞消融的时间和程度。因此，该方法可用于各种治疗应用，以及研究细胞系和器官发生加上残留干细胞用于再生的能力。

47. 发明授权

US06492137B1 Response element compositions and assays employing same 失效
标题翻译：响应元素组合物和采用其的测定法
公开(公告)号：US06492137B1
公开(公告)日：2002-12-10
申请号：US07672530
申请日：1991-03-19
申请人： Henry M. Sucov , Ronald M. Evans , Kazuhiko Umesono
发明人： Henry M. Sucov , Ronald M. Evans , Kazuhiko Umesono
IPC分类号： C12P2102
CPC分类号： C07K14/70567 , C07K14/721 , C12N15/85 , C12N2800/108 , C12N2830/002 , C12N2830/008 , C12N2830/30 , C12N2830/38 , C12N2830/60 , C12N2830/85 , C12Q1/6897 , G01N33/5008 , G01N33/502 , G01N33/5023 , G01N33/5041 , G01N33/743
摘要： DNA segments have been discovered, and characterized by sequence, which are response elements operative to confer responsiveness to ligands for several members of the steroid/thyroid superfamily of receptors, for the transcriptional activation and/or repression of promoters in cells. By using transcriptional control regions comprising response elements of the present invention in combination with a functional promoter, it is now possible to provide recombinant DNA vectors containing a gene, the transcription (and, thereby, also expression) of which is under the control of a promoter, the transcriptional activity of which is responsive to ligands for members of the steroid/thyroid superfamily of receptors.
摘要翻译：已经发现了DNA区段，其特征在于序列，其是作用于赋予类固醇/甲状腺超家族受体的若干成员对配体的反应性的响应元件，用于细胞中启动子的转录激活和/或抑制。通过使用包含本发明的响应元件与功能启动子组合的转录控制区，现在可以提供含有基因的重组DNA载体，其转录（并且由此也由其表达）处于一个启动子，其转录活性对受体的类固醇/甲状腺超家族成员的配体有反应。

48. 发明授权

US06489441B1 Transcriptional co-repressor that interacts with nuclear hormone receptors 失效
标题翻译：与核激素受体相互作用的转录共同抑制因子
公开(公告)号：US06489441B1
公开(公告)日：2002-12-03
申请号：US08522726
申请日：1995-09-01
申请人： Ronald M. Evans , J. Don Chen
发明人： Ronald M. Evans , J. Don Chen
IPC分类号： C07K14435
CPC分类号： C07K14/4703 , G01N33/74 , G01N2500/00
摘要： In accordance with the present invention, there are provided novel receptor interacting factors, referred to herein as “SMRT”, i.e., a silencing mediator (co-repressor) for retinoic acid receptor (RAR) and thyroid hormone receptor (TR). SMRT is a novel protein whose association with RAR and TR both in solution and on DNA response elements is destabilized by ligand. The interaction of SMRT with mutant receptors correlates with the transcriptional silencing activities of receptors. In vivo, SMRT functions as a potent co-repressor. A GAL4 DNA binding domain (DBD) fusion of SMRT behaves as a frank repressor of a GAL4-dependent reporter. Together, these data identify a novel class of cofactor which is believed to represent an important mediator of hormone action.
摘要翻译：根据本发明，提供了新颖的受体相互作用因子，本文称为“SMRT”，即视黄酸受体（RAR）和甲状腺激素受体（TR）的沉默介质（共抑制因子）。 SMRT是一种新的蛋白质，其与溶液中的RAR和TR在DNA响应元件上的配体不稳定。 SMRT与突变体受体的相互作用与受体的转录沉默活性相关。在体内，SMRT作为一种有效的共抑制剂。 SMRT的GAL4 DNA结合结构域（DBD）融合作为GAL4依赖性记录的坦率阻遏物。在一起，这些数据确定了一类新的辅因子，被认为代表激素作用的重要介质。

49. 发明授权

US06319663B1 Method for the identification and use of substances that modulate POD function and/or structure 失效
标题翻译：用于鉴定和使用调节POD功能和/或结构的物质的方法
公开(公告)号：US06319663B1
公开(公告)日：2001-11-20
申请号：US08975272
申请日：1997-11-21
申请人： Vassilis Doucas , Ronald M. Evans
发明人： Vassilis Doucas , Ronald M. Evans
IPC分类号： C12Q100
CPC分类号： G01N33/5011 , C12Q1/6897 , G01N33/5008 , G01N33/6875
摘要： The invention disclosed herein comprises assay methods for identifying substances useful for treating pathogenic disorders. The assay methods disclosed herein are based on the discovery that POD function and structure are key elements in normal transcriptional processes. Disruption of POD function and/or structure contributes to the creation and/or maintenance of a variety of pathogenic disorders.
摘要翻译：本文公开的发明包括用于鉴定可用于治疗病原性疾病的物质的测定方法。本文公开的测定方法基于POD功能和结构是正常转录过程中的关键元素的发现。 POD功能和/或结构的破坏有助于产生和/或维持各种致病性疾病。

50. 发明授权

US5968989A Means for the modulation of processes mediated by retinoid receptors and compounds useful therefor 失效
公开(公告)号：US5968989A
公开(公告)日：1999-10-19
申请号：US472817
申请日：1995-06-07
申请人： Ronald M. Evans , David J. Mangelsdorf , Richard A. Heyman , Marcus F. Boehm , Gregor Eichele , Christina Thaller
发明人： Ronald M. Evans , David J. Mangelsdorf , Richard A. Heyman , Marcus F. Boehm , Gregor Eichele , Christina Thaller
IPC分类号： A61K31/07 , A61K31/19 , A61K31/20 , A61K31/203 , A61K31/23 , A61K31/232 , A61K38/21 , C07C53/00 , C07C57/26 , C07C59/46 , C07C59/80 , C07K14/705 , C12P7/04 , A01N31/04 , A01N37/00
CPC分类号： C07K14/70567 , A61K31/07 , A61K31/19 , A61K31/20 , A61K31/203 , A61K31/23 , A61K31/232 , C07C403/20 , C07C57/26 , C07C59/46 , C07C59/80 , C12P7/04 , C07B2200/09 , C07C2101/16
摘要： In accordance with the present invention, there are provided methods to modulate processes mediated by retinoid receptors, employing high affinity, high specificity ligands for such receptors. In one aspect of the present invention, there are provided ligands which are more selective for the retinoid X receptor than is retinoic acid (i.e., rexoids). In another aspect of the present invention, alternative ligands (other than retinoic acid) have been discovered which are capable of inducing retinoic acid receptor mediated processes. In yet another aspect, methods have been developed for the preparation of such retinoid receptor ligands from readily available compounds.

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