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    Nucleotide and protein sequences of vertebrate delta genes and methods based thereon
    11.
    发明授权
    Nucleotide and protein sequences of vertebrate delta genes and methods based thereon 失效
    脊椎动物δ基因的核苷酸和蛋白质序列及其基础的方法

    公开(公告)号：US06783956B2

    公开(公告)日：2004-08-31

    申请号：US09908322

    申请日：2001-07-17

    申请人： David Ish-Horowicz ,  Domingos Manuel Pinto Henrique ,  Julian Hart Lewis ,  Spyridon Artavanis-Tsakonas ,  Grace E. Gray

    发明人： David Ish-Horowicz ,  Domingos Manuel Pinto Henrique ,  Julian Hart Lewis ,  Spyridon Artavanis-Tsakonas ,  Grace E. Gray

    IPC分类号： C12P2106

    CPC分类号： C07K14/47 ,  A61K38/00 ,  C07K14/705 ,  C07K2319/00

    摘要： The present invention relates to nucleotide sequences of vertebrate Delta genes, and amino acid sequences of their encoded proteins, as well as derivatives (e.g., fragments) and analogs thereof. In a specific embodiment, the vertebrate Delta protein is a human protein. The invention further relates to fragments (and derivatives and analogs thereof) of Delta which comprise one or more domains of the Delta protein, including but not limited to the intracellular domain, extracellular domain, DSL domain, domain amino-terminal to the DSL domain, transmembrane region, or one or more EGF-like repeats of a Delta protein, or any combination of the foregoing. Antibodies to Delta, its derivatives and analogs, are additionally provided. Methods of production of the Delta proteins, derivatives and analogs, e.g., by recombinant means, are also provided. Therapeutic and diagnostic methods and pharmaceutical compositions are provided. In specific examples, isolated Delta genes, from Xenopus, chick, mouse, and human, are provided.

    摘要翻译： 本发明涉及脊椎动物Delta基因的核苷酸序列，及其编码的蛋白质的氨基酸序列以及衍生物（例如片段）及其类似物。 在具体实施方案中，脊椎动物Delta蛋白是人蛋白质。 本发明还涉及包含Delta蛋白的一个或多个结构域的Delta的片段（及其衍生物和类似物），包括但不限于细胞内结构域，细胞外结构域，DSL结构域，DSL结构域的氨基末端， 跨膜区域，或Delta蛋白质的一种或多种EGF样重复序列或前述的任何组合。 额外提供了抗体对Delta，其衍生物和类似物。 还提供了通过重组方法生产Delta蛋白质，衍生物和类似物的方法。 提供了治疗和诊断方法和药物组合物。 在具体实例中，提供了来自爪蟾，小鸡，小鼠和人的孤立的Delta基因。

    Deltex proteins
    13.
    发明授权
    Deltex proteins 失效
    Deltex蛋白

    公开(公告)号：US5750652A

    公开(公告)日：1998-05-12

    申请号：US185432

    申请日：1994-01-21

    申请人： Spyridon Artavanis-Tsakonas ,  Isabelle Busseau ,  Robert J. Diederich ,  Tian Xu ,  Kenji Matsuno

    发明人： Spyridon Artavanis-Tsakonas ,  Isabelle Busseau ,  Robert J. Diederich ,  Tian Xu ,  Kenji Matsuno

    IPC分类号： A61K38/00 ,  C07H21/00 ,  C07K14/435 ,  C07K14/47 ,  C07K16/18 ,  C07K14/705

    CPC分类号： C07H21/00 ,  C07K14/435 ,  C07K14/47 ,  C07K16/18 ,  A61K38/00 ,  C07K2319/00

    摘要： The present invention relates to amino acid sequences of the encoded deltex protein. The invention further relates to fragments and other derivatives, and analogs, of deltex proteins. In specific embodiments, the invention relates to deltex protein derivatives and analogs of the invention which are functionally active, or which comprise one or more domains of a deltex protein, including but not limited to the Gln-rich clusters, SH3 binding domains, domains which mediate binding to Notch or to a Notch derivative containing Notch cdc10/SW16/ankyrin ("ANK") repeats, domains which mediate binding to a second deltex protein, or any combination of the foregoing. The present invention also relates to compositions based on deltex proteins.

    摘要翻译： 本发明涉及编码的deltex蛋白的氨基酸序列。 本发明还涉及deltex蛋白的片段和其他衍生物和类似物。 在具体实施方案中，本发明涉及在功能上有活性或包含一个或多个deltex蛋白结构域的本发明的脱胶蛋白衍生物和类似物，包括但不限于富含Gln的簇，SH3结合结构域， 介导与Notch或Notch cdc10 / SW16 / ankyrin（“ANK”）的Notch衍生物的结合重复，介导与第二个脱落蛋白结合的结构域，或上述的任何组合。 本发明还涉及基于脱胶蛋白的组合物。

    Activated Forms Of Notch And Methods Based Thereon
    14.
    发明申请
    Activated Forms Of Notch And Methods Based Thereon 失效
    激活形式的陷阱和方法基于此

    公开(公告)号：US20110028383A1

    公开(公告)日：2011-02-03

    申请号：US12789148

    申请日：2010-05-27

    申请人： Spyridon Artavanis-Tsakonas ,  Huilin Qi ,  Matthew D. Rand

    发明人： Spyridon Artavanis-Tsakonas ,  Huilin Qi ,  Matthew D. Rand

    IPC分类号： A61K38/02 ,  C12Q1/02 ,  G01N33/53 ,  C07K2/00 ,  A61P35/00

    CPC分类号： G01N33/5032 ,  C07K14/705 ,  G01N33/68 ,  G01N2500/10

    摘要： The present invention is directed to methods for detecting or measuring Notch activation by observing or measuring the appearance of Notch on the cell surface or by observing or measuring Notch cleavage products that are indicative of Notch activation. The present invention is also directed to methods for detecting a molecule that modulates Notch activation by observing or measuring a change in the amount of Notch expressed on the cell surface or a change in the amount or pattern of Notch cleavage products. The present invention is also directed to a substantially purified activated heterodimeric form of Notch and components thereof and pharmaceutical compositions and kits thereof. The present invention is based, at least in part, on the discovery that Notch in its active form, i.e., the form that mediates signal transduction and that binds Notch ligands such as Delta, is a heterodimer of an about 180 kDa subunit (NEC) and an about 110 kDa subunit (NTM), which are tethered together through a reducing agent-sensitive linkage, in particular, a non-covalent, metal ion-dependent linkage.

    摘要翻译： 本发明涉及通过观察或测量Notch在细胞表面上的外观或通过观察或测量Notch切割产物来表征Notch活化来检测或测量Notch活化的方法。 本发明还涉及通过观察或测量在细胞表面表达的Notch量的变化或Notch切割产物的量或图案的变化来检测调节Notch活化的分子的方法。 本发明还涉及基本上纯化的Notch及其组分的活化异二聚体形式及其药物组合物和试剂盒。 本发明至少部分地基于以下发现：Notch以其活性形式即介导信号转导并且结合Notch配体如Delta的形式是约180kDa亚基（NEC）的异源二聚体的发现， 和约110kDa的亚基（NTM），其通过还原剂敏感性连接键连在一起，特别是非共价金属离子依赖性连接。

    Methods for identifying modulators of Notch activation
    15.
    发明授权
    Methods for identifying modulators of Notch activation 有权
    识别Notch激活调节剂的方法

    公开(公告)号：US07727732B2

    公开(公告)日：2010-06-01

    申请号：US10781059

    申请日：2004-02-17

    申请人： Spyridon Artavanis-Tsakonas ,  Huilin Qi ,  Matthew D. Rand

    发明人： Spyridon Artavanis-Tsakonas ,  Huilin Qi ,  Matthew D. Rand

    IPC分类号： G01N33/567 ,  A01K67/033

    CPC分类号： G01N33/5032 ,  C07K14/705 ,  G01N33/68 ,  G01N2500/10

    摘要： The present invention is directed to methods for detecting or measuring Notch activation by observing or measuring the appearance of Notch on the cell surface or by observing or measuring Notch cleavage products that are indicative of Notch activation. The present invention is also directed to methods for detecting a molecule that modulates Notch activation by observing or measuring a change in the amount of Notch expressed on the cell surface or a change in the amount or pattern of Notch cleavage products. The present invention is also directed to a substantially purified activated heterodimeric form of Notch and components thereof and pharmaceutical compositions and kits thereof. The present invention is based, at least in part, on the discovery that Notch in its active form, i.e., the form that mediates signal transduction and that binds Notch ligands such as Delta, is a heterodimer of an about 180 kDa subunit (NEC) and an about 110 kDa subunit (NTM), which are tethered together through a reducing agent-sensitive linkage, in particular, a non-covalent, metal ion-dependent linkage.

    摘要翻译： 本发明涉及通过观察或测量Notch在细胞表面上的外观或通过观察或测量Notch切割产物来表征Notch活化来检测或测量Notch活化的方法。 本发明还涉及通过观察或测量在细胞表面表达的Notch量的变化或Notch切割产物的量或图案的变化来检测调节Notch活化的分子的方法。 本发明还涉及基本上纯化的Notch及其组分的活化异二聚体形式及其药物组合物和试剂盒。 本发明至少部分地基于以下发现：Notch以其活性形式即介导信号转导并且结合Notch配体如Delta的形式是约180kDa亚基（NEC）的异源二聚体的发现， 和约110kDa的亚基（NTM），其通过还原剂敏感性连接键连在一起，特别是非共价金属离子依赖性连接。

    Activated forms of notch and methods based thereon
    16.
    发明申请
    Activated forms of notch and methods based thereon 有权
    基于此的活化形式的缺口和方法

    公开(公告)号：US20070003983A1

    公开(公告)日：2007-01-04

    申请号：US10781059

    申请日：2004-02-17

    申请人： Spyridon Artavanis-Tsakonas ,  Huilin Qi ,  Matthew Rand

    发明人： Spyridon Artavanis-Tsakonas ,  Huilin Qi ,  Matthew Rand

    IPC分类号： G01N33/567 ,  A01K67/033

    CPC分类号： G01N33/5032 ,  C07K14/705 ,  G01N33/68 ,  G01N2500/10

    摘要： The present invention is directed to methods for detecting or measuring Notch activation by observing or measuring the appearance of Notch on the cell surface or by observing or measuring Notch cleavage products that are indicative of Notch activation. The present invention is also directed to methods for detecting a molecule that modulates Notch activation by observing or measuring a change in the amount of Notch expressed on the cell surface or a change in the amount or pattern of Notch cleavage products. The present invention is also directed to a substantially purified activated heterodimeric form of Notch and components thereof and pharmaceutical compositions and kits thereof. The present invention is based, at least in part, on the discovery that Notch in its active form, i.e., the form that mediates signal transduction and that binds Notch ligands such as Delta, is a heterodimer of an about 180 kDa subunit (NEC) and an about 110 kDa subunit (NTM), which are tethered together through a reducing agent-sensitive linkage, in particular, a non-covalent, metal ion-dependent linkage.

    摘要翻译： 本发明涉及通过观察或测量Notch在细胞表面上的外观或通过观察或测量Notch切割产物来表征Notch活化来检测或测量Notch活化的方法。 本发明还涉及通过观察或测量在细胞表面表达的Notch量的变化或Notch切割产物的量或图案的变化来检测调节Notch活化的分子的方法。 本发明还涉及基本上纯化的Notch及其组分的活化异二聚体形式及其药物组合物和试剂盒。 本发明至少部分地基于以下发现：Notch以其活性形式即介导信号转导并且结合Notch配体如Delta的形式是约180kDa亚基的异二聚体（N < SUP> EC）和约110kDa的亚基（N？TM），它们通过还原剂敏感性连接键连在一起，特别是非共价金属离子依赖性 连锁。

    Therapeutic and diagnostic methods and compositions based on notch proteins and nucleic acids
    17.
    发明授权
    Therapeutic and diagnostic methods and compositions based on notch proteins and nucleic acids 失效
    基于缺口蛋白和核酸的治疗和诊断方法和组合物

    公开(公告)号：US06083904A

    公开(公告)日：2000-07-04

    申请号：US532384

    申请日：1995-09-22

    申请人： Spyridon Artavanis-Tsakonas

    发明人： Spyridon Artavanis-Tsakonas

    IPC分类号： G01N33/53 ,  A01N37/18 ,  A61K31/70 ,  A61K38/00 ,  A61K38/17 ,  A61K39/395 ,  A61K48/00 ,  A61P1/16 ,  A61P17/00 ,  A61P25/00 ,  A61P35/00 ,  A61P43/00 ,  C07H21/04 ,  C07K14/435 ,  C07K14/47 ,  C07K14/705 ,  C12N1/21 ,  C12N15/09 ,  C12N15/62 ,  C12P21/02 ,  C12R1/19 ,  G01N33/574 ,  G01N33/68

    CPC分类号： A61K31/70 ,  C07K14/43581 ,  C07K14/47 ,  C07K14/705 ,  C12N15/62 ,  G01N33/57411 ,  G01N33/57415 ,  G01N33/57419 ,  G01N33/57484 ,  G01N33/6893 ,  A61K38/00 ,  C07K2319/00 ,  C07K2319/02 ,  C07K2319/03 ,  C07K2319/20 ,  C07K2319/23 ,  C07K2319/70 ,  C07K2319/95 ,  Y10S436/811 ,  Y10S436/813 ,  Y10S436/815

    摘要： The present invention relates to therapeutic and diagnostic methods and compositions based on Notch proteins and nucleic acids. The invention provides for treatment of disorders of cell fate or differentiation by administration of a therapeutic compound of the invention. Such therapeutic compounds (termed herein "Therapeutics") include Notch proteins and analogs and derivatives (including fragments) thereof, antibodies thereto, nucleic acids encoding the Notch proteins, analogs, or derivatives, Notch antisense nucleic acids, as well as toporythmic proteins and derivatives which bind to or otherwise interact with Notch proteins and their encoding nucleic acids and antibodies. In a preferred embodiment, a Therapeutic of the invention is administered to treat a cancerous condition, or to prevent progression from a pre-neoplastic or non-malignant state into a neoplastic or a malignant state. In other embodiments, a Therapeutic is administered to treat a nervous system disorder or to promote tissue regeneration and repair. In one embodiment, Therapeutics which antagonize, or inhibit, Notch function (hereinafter "Antagonist Therapeutics") are administered for therapeutic effect. In another embodiment, Therapeutics which promote Notch function (hereinafter "Agonist Therapeutics") are administered for therapeutic effect. Diagnostic methods and methods of inhibiting Notch expression are also provided.

    摘要翻译： 本发明涉及基于Notch蛋白和核酸的治疗和诊断方法和组合物。 本发明提供了通过施用本发明的治疗化合物治疗细胞命运或分化的病症。 此类治疗化合物（本文称为“治疗学”）包括Notch蛋白及其类似物和衍生物（包括其片段），其抗体，编码Notch蛋白，类似物或衍生物的核酸，Notch反义核酸以及拓扑蛋白和衍生物 其与Notch蛋白质及其编码核酸和抗体结合或以其它方式相互作用。 在优选的实施方案中，施用本发明的治疗剂以治疗癌症状况，或预防从肿瘤前或非恶性状态进展为肿瘤或恶性状态。 在其它实施方案中，施用治疗剂以治疗神经系统疾病或促进组织再生和修复。 在一个实施方案中，施用拮抗或抑制Notch功能的治疗剂（以下称为“拮抗剂治疗剂”）用于治疗效果。 在另一个实施方案中，施用促进Notch功能的治疗剂（以下称为“激动剂治疗剂”）用于治疗效果。 还提供了抑制Notch表达的诊断方法和方法。

    Human notch and delta, binding domains in toporythmic proteins, and methods based thereon
    18.
    发明授权
    Human notch and delta, binding domains in toporythmic proteins, and methods based thereon 失效
    人类缺口和δ，拓扑蛋白中的结合结构域，以及基于此的方法

    公开(公告)号：US5789195A

    公开(公告)日：1998-08-04

    申请号：US465500

    申请日：1995-06-05

    申请人： Spyridon Artavanis-Tsakonas ,  Marc Alan Telander Muskavitch ,  Richard Grant Fehon ,  Ilaria Rebay ,  Christine Marie Blaumueller ,  Scott Brockwell Shepard

    发明人： Spyridon Artavanis-Tsakonas ,  Marc Alan Telander Muskavitch ,  Richard Grant Fehon ,  Ilaria Rebay ,  Christine Marie Blaumueller ,  Scott Brockwell Shepard

    IPC分类号： A61K38/00 ,  C07K14/705 ,  C07K16/18 ,  C12N15/12 ,  C12N15/05

    CPC分类号： C07K16/18 ,  C07K14/705 ,  A61K38/00 ,  C07K2319/00 ,  Y10S530/839

    摘要： The present invention relates to nucleotide sequences of the human Notch and Delta genes, and amino acid sequences of their encoded proteins, as well as fragments thereof containing an antigenic determinant or which are functionally active. The invention is also directed to fragments (termed herein "adhesive fragments"), and the sequences thereof, of the proteins ("toporythmic proteins") encoded by toporythmic genes which mediate homotypic or heterotypic binding to toporythmic proteins. Toporythmic genes, as used herein, refers to the genes Notch, Delta, and Serrate, as well as other members of the Delta/Serrate family which may be identified, e.g., by the methods described herein. Analogs and derivatives of the adhesive fragments which retain-binding activity are also provided. Antibodies to human Notch and to adhesive fragments are additionally provided. In specific embodiments, the adhesive fragment of Notch is that fragment comprising the Notch sequence most homologous to Drosophila Notch EGF-like repeats 11 and 12; the adhesive fragment of Delta mediating heterotypic binding is that fragment comprising the sequence most homologous to Drosophila Delta amino acids 1-230; the adhesive fragment of Delta mediating homotypic binding is that fragment comprising the sequence most homologous to Drosophila Delta amino acids 32-230; and the adhesive fragment of Serrate is that fragment comprising the sequence most homologous to Drosophila Serrate amino acids 85-283.

    摘要翻译： 本发明涉及人Notch和Delta基因的核苷酸序列及其编码蛋白质的氨基酸序列，以及其含有抗原决定簇或其功能活性的片段。 本发明还涉及由介导与拓扑蛋白质的同型或异型结合的拓扑学基因编码的蛋白质（“拓扑蛋白”）的片段（称为“粘合片段”）及其序列。 如本文所用的拓扑学基因是指Notch，Delta和Serrate基因以及Delta / Serrate家族的其他成员，例如通过本文所述的方法鉴定。 还提供了保留结合活性的粘合剂片段的类似物和衍生物。 另外提供人类Notch和粘合剂片段的抗体。 在具体实施方案中，Notch的粘合片段是包含与果蝇Notch EGF样重复序列11和12最相似的Notch序列的片段; Delta介导异型结合的粘合片段是包含与果蝇Delta氨基酸1-230最相似的序列的片段; Delta介导同型结合的粘合片段是包含与果蝇三角洲氨基酸32-230最相似的序列的片段; 并且Serrate的粘合片段是包含与果糖果丝氨酸85-283最相似序列的片段。

    Nucleotide and protein sequences of vertebrate delta genes and methods based thereon
    20.
    发明申请
    Nucleotide and protein sequences of vertebrate delta genes and methods based thereon 失效
    脊椎动物δ基因的核苷酸和蛋白质序列及其基础的方法

    公开(公告)号：US20070134239A1

    公开(公告)日：2007-06-14

    申请号：US11546583

    申请日：2006-10-10

    申请人： David Ish-Horowicz ,  Domingos Henrique ,  Julian Lewis ,  Spyridon Artavanis-Tsakonas ,  Grace Gray

    发明人： David Ish-Horowicz ,  Domingos Henrique ,  Julian Lewis ,  Spyridon Artavanis-Tsakonas ,  Grace Gray

    IPC分类号： A61K39/395 ,  C07H21/04 ,  C12P21/06 ,  C07K14/705 ,  C07K16/30 ,  A61K38/17

    CPC分类号： C07K14/47 ,  A61K38/00 ,  C07K14/705 ,  C07K2319/00

    摘要： The present invention relates to nucleotide sequences of vertebrate Delta genes, and amino acid sequences of their encoded proteins, as well as derivatives (e.g., fragments) and analogs thereof. In a specific embodiment, the vertebrate Delta protein is a human protein. The invention further relates to fragments (and derivatives and analogs thereof) of Delta which comprise one or more domains of the Delta protein, including but not limited to the intracellular domain, extracellular domain, DSL domain, domain amino-terminal to the DSL domain, transmembrane region, or one or more EGF-like repeats of a Delta protein, or any combination of the foregoing. Antibodies to Delta, its derivatives and analogs, are additionally provided. Methods of production of the Delta proteins, derivatives and analogs, e.g., by recombinant means, are also provided. Therapeutic and diagnostic methods and pharmaceutical compositions are provided. In specific examples, isolated Delta genes, from Xenopus, chick, mouse, and human, are provided.

    摘要翻译： 本发明涉及脊椎动物Delta基因的核苷酸序列，及其编码的蛋白质的氨基酸序列以及衍生物（例如片段）及其类似物。 在具体实施方案中，脊椎动物Delta蛋白是人蛋白质。 本发明还涉及包含Delta蛋白的一个或多个结构域的Delta的片段（及其衍生物和类似物），包括但不限于细胞内结构域，细胞外结构域，DSL结构域，DSL结构域的氨基末端， 跨膜区域，或Delta蛋白质的一种或多种EGF样重复序列或前述的任何组合。 额外提供了抗体对Delta，其衍生物和类似物。 还提供了通过重组方法生产Delta蛋白质，衍生物和类似物的方法。 提供了治疗和诊断方法和药物组合物。 在具体实例中，提供了来自爪蟾，小鸡，小鼠和人的孤立的Delta基因。