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公开(公告)号：US07323439B2
公开(公告)日：2008-01-29
申请号：US09960708
申请日：2001-09-19
申请人： Gerald R. Crabtree , Isabella Graef , Feng Chen
发明人： Gerald R. Crabtree , Isabella Graef , Feng Chen
CPC分类号： A61K38/13 , G01N33/5011 , G01N33/6872 , G01N2500/02
摘要： Methods and compositions for modulating angiogenesis in a host are provided. In the subject methods, an effective amount of Ca2+/calcineurin/NF-ATc signaling pathway modulatory agent is administered to the host. In many embodiments, the Ca2+/calcineurin/NF-ATc signaling pathway modulatory agent is an NF-ATc antagonist, e.g., in those embodiments of inhibiting angiogenesis. The subject methods find use in a variety of different applications, including the inhibition of tumor growth and the treatment of disease conditions characterized by tumor presence. Also provided are methods of screening for agents that inhibit angiogenesis by modulating the Ca2+/calcineurin/NF-ATc signaling pathway.
摘要翻译： 提供了用于调节宿主中血管生成的方法和组合物。 在本方法中，向宿主施用有效量的Ca 2+ /钙调神经磷酸酶/ NF-ATc信号通路调节剂。 在许多实施方案中，Ca 2+ /钙调神经磷酸酶/ NF-ATc信号通路调节剂是NF-ATc拮抗剂，例如在抑制血管生成的那些实施方案中。 本发明的方法可用于各种不同的应用，包括抑制肿瘤生长和治疗以肿瘤存在为特征的疾病状况。 还提供了通过调节Ca 2+ /钙调神经磷酸酶/ NF-ATc信号通路来筛选抑制血管生成的药剂的方法。
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公开(公告)号：US07485706B2
公开(公告)日：2009-02-03
申请号：US10901848
申请日：2004-07-28
IPC分类号： C07D498/18 , C07D417/02 , C07D211/60 , C12N9/00 , C12Q1/00 , A01N37/18
CPC分类号： A61K31/4745 , A61K31/5415 , A61K31/655 , A61K31/7076 , A61K47/54
摘要： Methods and compositions are provided for reducing aggregation of neurodegenerative proteins associated with neurotoxicity or other proteins. The compounds comprise a first domain or targeting element for binding to the target proteins linked to a second domain or recruiting element that binds to an aggregation inhibiting protein, e.g. a prolyl isomerase. By associating the aggregating forming proteins or neuronal cells under conditions where aggregating proteins are produced with the compound and the aggregation inhibiting protein, aggregation is reduced. The subject agents can be used in assays, investigating the etiology of the neuronal diseases and for prophylaxis and therapy.
摘要翻译： 提供了用于减少与神经毒性相关的神经变性蛋白质的聚集或其它蛋白质的方法和组合物。 所述化合物包含用于结合靶向蛋白质的第一结构域或靶向元件，所述靶蛋白与结合至聚集抑制蛋白质的第二结构域或募集元件连接。 脯氨酰异构酶。 通过在与化合物和聚集抑制蛋白质产生聚集蛋白质的条件下将聚集形成蛋白质或神经元细胞缔合，减少聚集。 主题试剂可用于测定，研究神经元疾病的病因以及预防和治疗。
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公开(公告)号：US20080182792A1
公开(公告)日：2008-07-31
申请号：US12050017
申请日：2008-03-17
IPC分类号： A61K38/00
CPC分类号： A61K31/4745 , A61K31/5415 , A61K31/655 , A61K31/7076 , A61K47/54
摘要： Methods and compositions are provided for reducing aggregation of neurodegenerative proteins associated with neurotoxicity or other proteins. The compounds comprise a first domain or targeting element for binding to the target proteins linked to a second domain or recruiting element that binds to an aggregation inhibiting protein, e.g. a prolyl isomerase. By associating the aggregating forming proteins or neuronal cells under conditions where aggregating proteins are produced with the compound and the aggregation inhibiting protein, aggregation is reduced. The subject agents can be used in assays, investigating the etiology of the neuronal diseases and for prophylaxis and therapy.
摘要翻译： 提供了用于减少与神经毒性相关的神经变性蛋白质的聚集或其它蛋白质的方法和组合物。 所述化合物包含用于结合靶向蛋白质的第一结构域或靶向元件，所述靶蛋白与结合至聚集抑制蛋白质的第二结构域或募集元件连接。 脯氨酰异构酶。 通过在与化合物和聚集抑制蛋白质产生聚集蛋白质的条件下缔合形成蛋白质或神经元细胞，聚集减少。 主题试剂可用于测定，研究神经元疾病的病因以及预防和治疗。
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公开(公告)号：US06197925B1
公开(公告)日：2001-03-06
申请号：US08260174
申请日：1994-06-13
IPC分类号： C07K500
CPC分类号： A61K31/70 , A61K38/1709 , C07K14/4702 , C07K14/4705 , C12Q1/6876 , C12Q1/6897 , C12Q2600/158 , G01N33/6872 , G01N2500/02 , A61K2300/00
摘要： The invention provides novel polypeptides which are associated with the transcription complex NF-AT, polynucleotides encoding such polypeptides, antibodies which are reactive with such polypeptides, polynucleotide hybridization probes and PCR amplification probes for detecting polynucleotides which encode such polypeptides, transgenes which encode such polypeptides, homologous targeting constructs that encode such polypeptides and/or homologously integrate in or near endogenous genes encoding such polypeptides, nonhuman transgenic animals which comprise functionally disrupted endogenous genes that normally encode such polypeptides, and transgenic nonhuman animals which comprise transgenes encoding such polypeptides. The invention also provides methods for detecting T cells (including activated T cells) in a cellular sample, methods for treating hyperactive or hypoactive T cell conditions, methods for screening for immunomodulatory agents, methods for diagnostic staging of lymphocyte differentiation, methods for producing NF-AT proteins for use as research or diagnostic reagents, methods for producing antibodies reactive with the novel polypeptides, and methods for producing transgenic nonhuman animals.
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公开(公告)号：US6063625A
公开(公告)日：2000-05-16
申请号：US156855
申请日：1998-09-16
申请人： Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Steffan N. Ho , Peter Belshaw
发明人： Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Steffan N. Ho , Peter Belshaw
IPC分类号： A61K38/00 , A61K47/48 , C07D498/18 , C07F5/02 , C07H19/01 , C07K7/64 , C07K14/395 , C07K14/705 , C07K14/71 , C07K14/725 , C12N15/62 , C12N15/63 , C12P15/00 , C12N15/00 , C12N15/85 , C12N15/86
CPC分类号： C07D498/18 , A61K47/48276 , C07F5/025 , C07H19/01 , C07K14/395 , C07K14/705 , C07K14/7051 , C07K14/71 , C07K7/645 , C12N15/62 , C12N15/63 , C12P15/00 , A61K38/00 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C07K2319/035 , C07K2319/09 , C07K2319/20 , C07K2319/32 , C07K2319/42 , C07K2319/43 , C07K2319/60 , C07K2319/71 , C07K2319/715 , C07K2319/81 , C07K2319/90
摘要： Dimerization and oligomerization of proteins are general biological control mechanisms that contribute to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins. In principle, any two target proteins can be induced to associate by treating the cells or organisms that harbor them with cell permeable, synthetic ligands. To illustrate the practice of this invention, we have induced: (1) the intracellular aggregation of the cytoplasmic tail of the .zeta. chain of the T cell receptor (TCR)-CD3 complex thereby leading to signaling and transcription of a reporter gene, (2) the homodimerization of the cytoplasmic tail of the Fas receptor thereby leading to cell-specific apoptosis (programmed cell death) and (3) the heterodimerization of a DNA-binding domain (Gal4) and a transcription-activation domain (VP16) thereby leading to direct transcription of a reporter gene. Regulated intracellular protein association with our cell permeable, synthetic ligands offers new capabilities in biological research and medicine, in particular, in gene therapy. Using gene transfer techniques to introduce our artificial receptors, one can turn on or off the signaling pathways that lead to the overexpression of therapeutic proteins by administering orally active "dimerizers" or "de-dimerizers", respectively. Since cells from different recipients can be configured to have the pathway overexpress different therapeutic proteins for use in a variety of disorders, the dimerizers have the potential to serve as "universal drugs". They can also be viewed as cell permeable, organic replacements for therapeutic antisense agents or for proteins that would otherwise require intravenous injection or intracellular expression (e.g., the LDL receptor or the CFTR protein).
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公开(公告)号：US6046047A
公开(公告)日：2000-04-04
申请号：US157230
申请日：1998-09-16
申请人： Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw , Steffan N. Ho
发明人： Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw , Steffan N. Ho
IPC分类号： A61K38/00 , A61K47/48 , A61K48/00 , C07D498/18 , C07F5/02 , C07H19/01 , C07K7/64 , C07K14/395 , C07K14/705 , C07K14/71 , C07K14/715 , C07K14/725 , C12N15/12 , C12N15/62 , C12N15/63 , C12P15/00 , C12P17/18 , C12N15/13 , C12N15/85
CPC分类号： C07D498/18 , A61K47/48276 , A61K48/00 , C07F5/025 , C07H19/01 , C07K14/395 , C07K14/705 , C07K14/7051 , C07K14/71 , C07K14/715 , C07K7/645 , C12N15/62 , C12N15/63 , C12P15/00 , C12P17/188 , A01K2217/05 , A61K38/00 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C07K2319/035 , C07K2319/09 , C07K2319/20 , C07K2319/32 , C07K2319/42 , C07K2319/43 , C07K2319/60 , C07K2319/71 , C07K2319/715 , C07K2319/81 , C07K2319/90
摘要： Dimerization and oligomerization of proteins are general biological control mechanisms that contribute to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins. In principle, any two target proteins can be induced to associate by treating the cells or organisms that harbor them with cell permeable, synthetic ligands. To illustrate the practice of tis invention, we have induced: (1) the intracellular aggregation of the cytoplasmic tail of the .zeta. chain of the T cell receptor (TCR)-CD3 complex thereby leading to signaling and transcription of a reporter gene, (2) the homodimerization of the cytoplasmic tail of the Fas receptor thereby leading to cell-specific apoptosis (programmed cell death) and (3) the heterodimerization of a DNA-binding domain (Gal4) and a transcription-activation domain (VP16) thereby leading to direct transcription of a reporter gene. Regulated intracellular protein association with our cell permeable, synthetic ligands offers new capabilities in biological research and medicine, in particular, in gene therapy. Using gene transfer techniques to introduce our artificial receptors, one can turn on or off the signaling pathways that lead to the overexpression of therapeutic proteins by administering orally active "dimerizers" or "de-dimerizers", respectively. Since cells from different recipients can be configured to have the pathway overexpress different therapeutic proteins for use in a variety of disorders, the dimerizers have the potential to serve as "universal drugs". They can also be viewed as cell permeable, organic replacements for therapeutic antisense agents or for proteins that would otherwise require intravenous injection or intracellular expression (e.g., the LDL receptor or the CFTR protein).
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公开(公告)号：US06011018A
公开(公告)日：2000-01-04
申请号：US87716
申请日：1998-05-29
申请人： Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw
发明人： Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw
IPC分类号： A61K38/00 , A61K47/48 , A61K48/00 , C07D498/18 , C07F5/02 , C07H19/01 , C07K7/64 , C07K14/395 , C07K14/705 , C07K14/71 , C07K14/715 , C07K14/725 , C12N15/12 , C12N15/62 , C12N15/63 , C12P15/00 , C12P17/18 , A61K31/70 , A61K38/13
CPC分类号： C07D498/18 , A61K47/48276 , A61K48/00 , C07F5/025 , C07H19/01 , C07K14/395 , C07K14/705 , C07K14/7051 , C07K14/71 , C07K14/715 , C07K7/645 , C12N15/62 , C12N15/63 , C12P15/00 , C12P17/188 , A01K2217/05 , A61K38/00 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C07K2319/035 , C07K2319/09 , C07K2319/20 , C07K2319/32 , C07K2319/42 , C07K2319/43 , C07K2319/60 , C07K2319/71 , C07K2319/715 , C07K2319/81 , C07K2319/90
摘要： Dimerization and oligomerization of proteins are general biological control mechanisms that contribute to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins. In principle, any two target proteins can be induced to associate by treating the cells or organisms that harbor them with cell permeable, synthetic ligands. To illustrate the practice of this invention, we have induced: (1) the intracellular aggregation of the cytoplasmic tail of the .zeta. chain of the T cell receptor (TCR)-CD3 complex thereby leading to signaling and transcription of a reporter gene, (2) the homodimerization of the cytoplasmic tail of the Fas receptor thereby leading to cell-specific apoptosis (programmed cell death) and (3) the heterodimerization of a DNA-binding domain (Gal4) and a transcription-activation domain (VP16) thereby leading to direct transcription of a reporter gene. Regulated intracellular protein association with our cell permeable, synthetic ligands offers new capabilities in biological research and medicine, in particular, in gene therapy. Using gene transfer techniques to introduce our artificial receptors, one can turn on or off the signaling pathways that lead to the overexpression of therapeutic proteins by administering orally active "dimerizers" or "de-dimerizers", respectively. Since cells from different recipients can be configured to have the pathway overexpress different therapeutic proteins for use in a variety of disorders, the dimerizers have the potential to serve as "universal drugs". They can also be viewed as cell permeable, organic replacements for therapeutic antisense agents or for proteins that would otherwise require intravenous injection or intracellular expression (e.g., the LDL receptor or the CFTR protein).
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公开(公告)号：US5403712A
公开(公告)日：1995-04-04
申请号：US156383
申请日：1993-11-22
申请人： Gerald R. Crabtree , Dirk B. Mendel
发明人： Gerald R. Crabtree , Dirk B. Mendel
CPC分类号： C12N15/67 , C07K14/4702 , C07K2319/00 , C07K2319/61 , C07K2319/71 , C07K2319/81
摘要： Methods and compositions are provided for producing and utilizing nucleic acid and peptide sequences associated with cofactors which bind to transcription factors to enhance transcriptional activity of the transcriptional factors and maintain the transcriptional factors as dimers. The compositions can be used for modulating expression of genes, particularly coordinately regulated genes, as evidenced by the combination of the transcription factors HNF-1.alpha. and -1.beta. with the cofactor DCoH.
摘要翻译： 提供了用于产生和利用与与转录因子结合的辅因子相关联的核酸和肽序列以提高转录因子的转录活性并将转录因子维持为二聚体的方法和组合物。 如通过转录因子HNF-1α和-1β与辅因子DCoH的组合所证明的，组合物可用于调节基因，特别是配位调节基因的表达。
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公开(公告)号：US10976320B2
公开(公告)日：2021-04-13
申请号：US14284324
申请日：2014-05-21
IPC分类号： G01N33/574 , A61K31/352 , A61K31/704 , A61K31/496 , C12Q1/6886 , A61K31/475 , A61K31/473 , A61K31/05 , A61K31/136 , A61K31/353 , A61K31/7048
摘要： Methods for identifying and treating cancer patients likely to respond to topoisomerase inhibitors or likely to fail to respond to topoisomerase inhibitors are provided. The methods take advantage of the newly discovered role of BAF complexes in decatenation of DNA by topoisomerase IIa. Cancer cells are frequently at least partly defective in BAF complex activity. Such cells are targeted for therapy using certain topoisomerase IIa inhibitors according to the disclosed methods of treatment. Therapy of such cells using other topoisomerase inhibitors should be avoided.
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公开(公告)号：US20120277111A1
公开(公告)日：2012-11-01
申请号：US13441673
申请日：2012-04-06
申请人： Gerald R. Crabtree , Andrew Yoo
发明人： Gerald R. Crabtree , Andrew Yoo
IPC分类号： C12N5/0793 , C12Q1/68 , G01N27/26 , G01N33/566 , C12N15/85 , C40B30/04
CPC分类号： G01N33/5058 , C12N5/0619 , C12N15/113 , C12N2310/141 , C12N2501/48 , C12N2501/65 , C12N2506/1307 , C12N2510/00 , C12N2740/16043
摘要： Methods of converting non-neuronal somatic cells into induced neuronal cells are provided. Aspects of the methods include contacting a non-neuronal somatic cell with a microRNA mediated neuronal cell induction agent. Aspects of the invention further include compositions produced by methods of the invention as well as compositions that find use in practicing embodiments of methods of invention. The methods and compositions find use in a variety of different applications.
摘要翻译： 提供了将非神经元体细胞转化为诱导的神经元细胞的方法。 方法的方面包括使非神经元体细胞与微RNA介导的神经元细胞诱导剂接触。 本发明的方面还包括通过本发明的方法制备的组合物以及在实践本发明方法的实施方案中使用的组合物。 方法和组合物可用于各种不同的应用。
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