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21.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。
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公开(公告)号：US5780300A
公开(公告)日：1998-07-14
申请号：US537210
申请日：1995-09-29
IPC分类号： C12N15/09 , A61K31/00 , A61K35/12 , A61K38/00 , A61K39/395 , A61K45/00 , A61K48/00 , A61P43/00 , C07K14/47 , C12N5/00 , C12N5/07 , C12N5/0797 , C12N5/10 , C12P21/02 , C12N5/08 , C12N5/02 , C12N5/06
CPC分类号： C12N5/0623 , C07K14/47 , C12N5/0018 , C12N5/0601 , A61K35/12 , A61K38/00 , C12N2501/42
摘要： The present invention is directed to methods for the expansion of non-terminally differentiated cells ("precursor cells") using agonists of Notch function, by inhibiting the differentiation of the cells without inhibiting proliferation (mitotic activity) such that an expanded population of non-terminally differentiated cells is obtained. The cells are preferably stem or progenitor cells. These expanded cells can be used in cell replacement therapy to provide desired cell populations and help in the regeneration of diseased and/or injured tissues. The expanded cell populations can also be made recombinant and used for gene therapy, or can be used to supply functions associated with a particular precursor cell or its progeny cell.
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23.发明申请Manipulation of non-terminally differentiated cells using the Notch pathway 审中-公开使用Notch途径操纵非终末分化细胞公开(公告)号：US20050158859A1
公开(公告)日：2005-07-21
申请号：US10746237
申请日：2003-12-22
CPC分类号： C07K14/47 , A61K35/12 , A61K38/00 , C12N5/0018 , C12N5/0601 , C12N2501/42
摘要： The present invention is directed to methods for the expansion of non-terminally differentiated cells (“precursor cells”) using agonists of Notch function, by inhibiting the differentiation of the cells without inhibiting proliferation (mitotic activity) such that an expanded population of non-terminally differentiated cells is obtained. The cells are preferably stem or progenitor cells. These expanded cells can be used in cell replacement therapy to provide desired cell populations and help in the regeneration of diseased and/or injured tissues. The expanded cell populations can also be made recombinant and used for gene therapy, or can be used to supply functions associated with a particular precursor cell or its progeny cell.
摘要翻译： 本发明涉及使用Notch功能的激动剂来扩增非终末分化的细胞（“前体细胞”）的方法，通过抑制细胞的分化而不抑制增殖（有丝分裂活性），使得扩增的非 - 得到终末分化的细胞。 细胞优选是干细胞或祖细胞。 这些扩展的细胞可用于细胞替代疗法以提供所需的细胞群体并有助于患病和/或损伤组织的再生。 扩增的细胞群体也可以重组并用于基因治疗，或可用于提供与特定前体细胞或其后代细胞相关的功能。
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公开(公告)号：US06692919B1
公开(公告)日：2004-02-17
申请号：US09121457
申请日：1998-07-23
IPC分类号： G01N3353
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 < EC>）和约110kDa的亚基（N TM），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。
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公开(公告)号：US06436650B1
公开(公告)日：2002-08-20
申请号：US08899232
申请日：1997-07-23
IPC分类号： G01N33567
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.
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亚基（NTM），其通过还原剂敏感性连接物连接在一起。
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公开(公告)号：US5856441A
公开(公告)日：1999-01-05
申请号：US346128
申请日：1994-11-28
IPC分类号： A61K38/00 , C07K14/705 , C07K16/18
CPC分类号： C07K14/705 , C07K16/18 , A61K38/00 , C07K2319/00
摘要： The present invention relates to sequences of the serrate amino acid sequence as well as fragments thereof, and fragments which retain binding activity are also provided.
摘要翻译： 本发明涉及锯齿状氨基酸序列及其片段的序列，还提供了保留结合活性的片段。
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27.发明授权Human Notch and Delta binding domains in toporythmic proteins, and methods based thereon 失效拓扑学蛋白质中的人类Notch和Delta结合结构域，以及基于此的方法
公开(公告)号：US5648464A
公开(公告)日：1997-07-15
申请号：US264534
申请日：1994-06-23
IPC分类号： A61K38/00 , C07K14/705 , C07K16/18 , C07K14/435
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。
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28.发明授权Therapeutic and diagnostic methods and compositions based on transducin-like enhancer of split proteins and nucleic acids 失效基于分裂蛋白和核酸的转导素样增强子的治疗和诊断方法和组合物
公开(公告)号：US5637471A
公开(公告)日：1997-06-10
申请号：US385207
申请日：1995-02-07
CPC分类号： C07K14/47 , C07K14/4722 , G01N33/57407 , G01N33/57411 , G01N33/57415 , G01N33/5743 , G01N33/6881 , A61K38/00 , A61K48/00 , G01N2333/4719 , Y10S436/813
摘要： The present invention relates to diagnostic methods and compositions based on transducin-like Enhancer of split ("TLE") proteins and nucleic acids. The invention provides for aiding in the diagnosis of disorders of cell fate or differentiation by determining the level of transducin-like Enhancer of Split (TLE) proteins.
摘要翻译： 本发明涉及基于分解（“TLE”）蛋白和核酸的转导素样增强子的诊断方法和组合物。 本发明通过测定分解（TLE）蛋白质的转导素样增强子的水平来帮助诊断细胞命运或分化的病症。
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公开(公告)号：US20150291681A1
公开(公告)日：2015-10-15
申请号：US14388598
申请日：2012-03-29
IPC分类号： C07K14/705 , C07K16/28
CPC分类号： C07K14/705 , A61K38/00 , C07K14/43581 , C07K16/28 , C07K2317/30 , C07K2317/76 , C07K2319/30
摘要： Provided herein are polypeptides and derivatives thereof that contain sequences of a Serrate protein and that inhibit Notch pathway function. Also provided herein are nucleic acids that encode the polypeptides, vectors and cells for producing the polypeptides, and related pharmaceutical compositions and kits. Additionally provided are antibodies which bind to the Notch inhibitory region of a Serrate protein. Therapeutic methods are also provided.
摘要翻译： 本文提供含有Serrate蛋白序列并抑制Notch途径功能的多肽及其衍生物。 本文还提供了编码多肽的核酸，用于产生多肽的载体和细胞，以及相关的药物组合物和试剂盒。 另外提供了结合丝氨酸蛋白的Notch抑制区的抗体。 还提供了治疗方法。
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公开(公告)号：US08222213B2
公开(公告)日：2012-07-17
申请号：US12789148
申请日：2010-05-27
IPC分类号： A61K38/00 , G01N33/567 , C07K1/00
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。
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