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    Steroid-activated nuclear receptors and uses therefor
    2.
    发明授权
    Steroid-activated nuclear receptors and uses therefor 有权
    类固醇激活的核受体及其用途

    公开(公告)号：US07972782B2

    公开(公告)日：2011-07-05

    申请号：US11495263

    申请日：2006-07-27

    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多种治疗目标。 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。

    Retinoid receptor compositions and methods
    3.
    发明授权
    Retinoid receptor compositions and methods 失效
    类视黄醇受体组合物和方法

    公开(公告)号：US07501487B1

    公开(公告)日：2009-03-10

    申请号：US08467543

    申请日：1995-06-05

    申请人： David J. Mangelsdorf ,  Ronald M. Evans

    发明人： David J. Mangelsdorf ,  Ronald M. Evans

    IPC分类号： A07K14/00

    CPC分类号： C07K14/70567 ,  C12N15/64 ,  C12N15/67 ,  C12N15/85 ,  C12N2830/00 ,  C12N2830/002

    摘要： The present invention relates to novel receptor polypeptides, which, upon interaction with certain ligands, or activation by certain compounds, modulate transcription of certain genes by binding to cognate response elements associated with promoters of such genes. The novel receptors of the invention modulate transcription in the presence of retinoid compounds.The receptors of the present invention differ significantly from known retinoic acid receptors, in protein primary sequence and in responsiveness to exposure to various retinoids.The invention provides DNAs encoding the novel receptors, expression vectors for expression of the receptors, cells transformed with such expression vectors, cells co-transformed with such expression vectors and with reporter vectors to monitor modulation of transcription by the receptors, and methods of using such co-transformed cells in screening for compounds which are capable, directly or indirectly, of activating the receptors.The invention also provides nucleic acid probes for identifying DNAs which encode additional retinoid receptors of the same class as the novel receptors disclosed herein.

    摘要翻译： 本发明涉及新的受体多肽，其在与某些配体相互作用或某些化合物的活化时，通过结合与这些基因的启动子相关的同源反应元件来调节某些基因的转录。 本发明的新受体在类视色素化合物存在下调节转录。 本发明的受体与已知的视黄酸受体显着不同，蛋白质一级序列和对各种类视黄醇的暴露反应。 本发明提供了编码新受体的DNA，用于表达受体的表达载体，用这种表达载体转化的细胞，用这些表达载体共转化的细胞和用报道载体监测受体转录的调节的方法 共转化细胞筛选能够直接或间接激活受体的化合物。 本发明还提供用于鉴定编码与本文公开的新型受体相同类别的另外的类视黄醇受体的DNA的核酸探针。

    Hormone receptor compositions and methods
    4.
    发明授权
    Hormone receptor compositions and methods 失效
    激素受体组合物和方法

    公开(公告)号：US07214511B1

    公开(公告)日：2007-05-08

    申请号：US08464262

    申请日：1995-06-05

    申请人： Ronald M. Evans ,  Cary A. Weinberger ,  Stanley M. Hollenberg ,  Estelita S. Ong

    发明人： Ronald M. Evans ,  Cary A. Weinberger ,  Stanley M. Hollenberg ,  Estelita S. Ong

    IPC分类号： C12N15/12

    CPC分类号： C12Q1/6897 ,  C07K14/721 ,  C07K14/723 ,  C12N15/67

    摘要： In accordance with the present invention, there are provided expression systems for the production of function glucocorticoid receptor proteins, methods for the recombinant production of glucocorticoid receptor proteins as well as sequences encoding novel members of the steroid/thyroid hormone superfamily of receptors (e.g., glucocorticoid receptor). Invention expression systems comprise host cells containing DNA encoding functional glucocorticoid receptor proteins, wherein the DNA is operably linked to control sequences compatible with host cells, thereby enabling the expression of functional receptor proteins. The invention method is carried out by culturing such recombinant host cells, and recovering the functional glucocorticoid receptor proteins produced thereby. In accordance with the present invention, there are also provided substantially pure DNA's comprised of sequences which encode members of the steroid/thyroid hormone receptor superfamily having the hormone-binding and/or transcription-activating characteristics of a glucocorticoid receptor. The invention also provides various plasmids containing receptor sequences which exemplify the DNA's of the invention. The invention further provides receptor proteins, including modified functional forms thereof, expressed from the DNA's (or mRNA's) of the invention.

    摘要翻译： 根据本发明，提供了用于产生功能性糖皮质激素受体蛋白质的表达系统，重组生产糖皮质激素受体蛋白质的方法以及编码受体类固醇/甲状腺激素超家族的新成员的序列（例如，糖皮质激素 受体）。 本发明表达系统包含含有编码功能性糖皮质激素受体蛋白质的DNA的宿主细胞，其中所述DNA可操作地连接到与宿主细胞相容的控制序列，从而使得能够表达功能性受体蛋白质。 本发明方法是通过培养这样的重组宿主细胞进行的，并且回收由此产生的功能性糖皮质激素受体蛋白质。 根据本发明，还提供了基本上纯的DNA，其由编码具有糖皮质激素受体的激素结合和/或转录激活特性的类固醇/甲状腺激素受体超家族成员的序列组成。 本发明还提供了含有受体序列的各种质粒，其例证了本发明的DNA。 本发明还提供了从本发明的DNA（或mRNA）表达的受体蛋白，包括其修饰的功能形式。

    Hormone receptor compositions and methods
    5.
    发明授权
    Hormone receptor compositions and methods 失效
    激素受体组合物和方法

    公开(公告)号：US06794160B1

    公开(公告)日：2004-09-21

    申请号：US08462817

    申请日：1995-06-05

    申请人： Ronald M. Evans ,  Cary A. Weinberger ,  Stanley M. Hollenberg ,  Vincent Giguere ,  Jeffrey Arriza ,  Catherine C. Thompson ,  Estelita S. Ong

    发明人： Ronald M. Evans ,  Cary A. Weinberger ,  Stanley M. Hollenberg ,  Vincent Giguere ,  Jeffrey Arriza ,  Catherine C. Thompson ,  Estelita S. Ong

    IPC分类号： C12N1512

    CPC分类号： C12Q1/6897 ,  C07K14/721 ,  C07K14/723 ,  C12N15/67

    摘要： The present invention provides substantially pure DNA's comprised of sequences which encode proteins having the hormone-binding and/or transcription-activating characteristics of a glucocorticoid receptor, a mineralocorticoid receptor, or a thyroid hormone receptor; various plasmids containing receptor sequences which exemplify these DNA's; receptor proteins, including modified functional forms thereof, expressed from these DNA's (or mRNA's); and a bioassay for determining the functionality of a receptor protein. Use of this bioassay has led to the discovery that a necessary and sufficient condition for activation of transcription of a gene (G), whose transcription is activated by hormones complexed with receptors, is the presence of the hormone and its receptor cell (C) where (G) is located. As a result, two new methods for producing desired proteins in genetically engineered cells were discovered.

    摘要翻译： 本发明提供基本上纯的DNA，其由编码具有糖皮质激素受体，盐皮质激素受体或甲状腺激素受体的激素结合和/或转录激活特征的蛋白质的序列组成; 含有例证这些DNA的受体序列的各种质粒; 受体蛋白，包括其修饰的功能形式，由这些DNA（或mRNA）表达; 以及用于测定受体蛋白质功能的生物测定。 这种生物测定的使用已经导致发现，用于激活基因（G）的转录的必需和充分条件（G），其转录由与受体复合的激素激活，是激素及其受体细胞（C）的存在，其中 （G）位于。 因此，发现了两种在遗传工程细胞中产生所需蛋白质的新方法。

    Treatment of disease states which result from neoplastic cell proliferation using PPAR-&ggr; activators and compositions useful therefor
    6.
    发明授权
    Treatment of disease states which result from neoplastic cell proliferation using PPAR-&ggr; activators and compositions useful therefor 失效
    使用PPAR-γ激活剂和对其有用的组合物治疗由肿瘤细胞增殖引起的疾病状态

    公开(公告)号：US06646008B1

    公开(公告)日：2003-11-11

    申请号：US09331535

    申请日：2000-02-22

    申请人： Ronald M. Evans ,  Peter Tontonoz ,  Laszlo Nagy

    发明人： Ronald M. Evans ,  Peter Tontonoz ,  Laszlo Nagy

    IPC分类号： A61K3119

    CPC分类号： A61K31/44 ,  A61K31/12 ,  A61K31/19 ,  A61K31/192 ,  A61K31/205 ,  A61K31/445 ,  A61K31/557 ,  A61K31/5575 ,  A61K2300/00

    摘要： In accordance with the present invention, it has been discovered that PPAR&ggr; is expressed consistently in tissues associated with each of a variety of disease states which result from neoplastic cell proliferation. It has further been discovered that maximal activation of PPAR&ggr; with exogenous ligand promotes terminal differentiation of primary cells which are otherwise subject to neoplastic cell proliferation. In accordance with another aspect of the invention, it has been discovered that RXR-specific ligands are also potent agents for induction of differentiation of cells expressing the PPAR&ggr;/RXR&agr; heterodimer, and that simultaneous treatment of cells subject to neoplastic cell proliferation with a PPAR&ggr;-selective ligand, in combination with an RXR-specific ligand, results in an additive stimulation of differentiation. Thus, the effect of neoplastic cell proliferation can be ameliorated by treatment of cells undergoing neoplastic cell proliferation with PPAR&ggr; agonists, optionally in the further presence of RXR agonists, thereby blocking further proliferation thereof. Accordingly, compounds and compositions which are useful for the treatment of a variety of disease states which result from neoplastic cell proliferation have been identified and are described herein.

    摘要翻译： 根据本发明，已经发现，PPARγ在与由肿瘤细胞增殖引起的各种疾病状态中的每一种相关的组织中一致地表达。 进一步发现，具有外源性配体的PPARγ的最大活化促进了另外受到肿瘤细胞增殖的原代细胞的终末分化。 根据本发明的另一方面，已经发现RXR特异性配体也是用于诱导表达PPARγ/RXRα异源二聚体的细胞分化的有效试剂，并且用PPARγ- 选择性配体与RXR特异性配体组合导致分化的加性刺激。 因此，可以通过用PPARγ激动剂处理经历赘生性细胞增殖的细胞，任选地在RXR激动剂的进一步存在下，可以改善肿瘤细胞增殖的作用，从而阻断其进一步增殖。 因此，已经鉴定并描述了可用于治疗由肿瘤细胞增殖引起的各种疾病状态的化合物和组合物。

    Heterodimer complex of RXR and NURR1 or NGFI-B
    7.
    发明授权
    Heterodimer complex of RXR and NURR1 or NGFI-B 失效
    RXR和NURR1或NGFI-B的异二聚体复合物

    公开(公告)号：US06458926B1

    公开(公告)日：2002-10-01

    申请号：US08877966

    申请日：1997-06-18

    申请人： Ronald M. Evans ,  Barry M. Forman ,  Kazuhiko Umesono

    发明人： Ronald M. Evans ,  Barry M. Forman ,  Kazuhiko Umesono

    IPC分类号： C07K14435

    CPC分类号： C07K14/70567 ,  C07K2319/00 ,  G01N33/6875 ,  G01N33/74

    摘要： Heterodimerization is a common paradigm among eucaryotic transcription factors, though it remains unclear how individual monomers contribute to the overall transcriptional activities of the complex. The 9-cis retinoic acid receptor (RXR) serves as a common heterodimerization partner for several nuclear receptors including the thyroid hormone (T3R), retinoic acid (RAR) and vitamin D receptors. A strategy has been devised to examine the transcriptional properties of each receptor individually or when tethered to a heterodimeric partner. It has been found that the intrinsic activity of RXR is masked in RXR-T3R and RXR-RAR heterodimers. In contrast, a novel RXR-Nurr1 heterodimer described herein is highly responsive to RXR ligands, suggesting that different partners exert unique allosteric control over the RXR response. These findings establish a novel 9-cis retinoic acid response pathway and resolve the paradox as to how T3R, RAR and VDR contribute to distinct physiologic pathways while sharing a common RXR subunit.

    摘要翻译： 异源二聚化是真核转录因子中的常见范例，尽管单个单体如何有助于复合物的整体转录活性仍不清楚。 9-顺式视黄酸受体（RXR）用作几种核受体（包括甲状腺激素（T3R），视黄酸（RAR）和维生素D受体）的常见异源二聚体配偶体。 已经设计出一种策略来单独检测每个受体的转录特性，或者当连接到异二聚体配偶体时。 已经发现在RXR-T3R和RXR-RAR异二聚体中RXR的固有活性被掩蔽。 相比之下，本文描述的新型RXR-Nurr1异源二聚体对RXR配体具有高度响应性，表明不同的合作伙伴对RXR应答发挥独特的变构控制。 这些研究结果建立了一种新的9-顺式视黄酸反应途径，并解决了T3R，RAR和VDR如何在共享一个共同的RXR亚基时对不同的生理途径有贡献的矛盾。