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    ONCOGENOMICS-BASED RNAi SCREEN AND USE THEREOF TO IDENTIFY NOVEL TUMOR SUPPRESSORS
    1.
    发明申请
    ONCOGENOMICS-BASED RNAi SCREEN AND USE THEREOF TO IDENTIFY NOVEL TUMOR SUPPRESSORS 审中-公开
    基于ONCOGENOMICS的RNAi筛选及其用于鉴定新型肿瘤抑制剂

    公开(公告)号：US20100273660A1

    公开(公告)日：2010-10-28

    申请号：US12617624

    申请日：2009-11-12

    申请人： Lars Zender ,  Wen Xue ,  Scott Powers ,  Scott W. Lowe

    发明人： Lars Zender ,  Wen Xue ,  Scott Powers ,  Scott W. Lowe

    IPC分类号： C40B20/06 ,  C07K16/00 ,  C40B50/04 ,  C40B40/06 ,  C12N5/09 ,  C12Q1/68 ,  G01N33/574

    CPC分类号： A01K67/0271 ,  A01K2217/058 ,  A01K2267/0331 ,  C07K14/4747 ,  C12N15/1079 ,  C12N15/8509 ,  C12N2510/04 ,  C12N2517/02 ,  C12N2799/027 ,  C12Q1/6886 ,  C12Q2600/154 ,  C12Q2600/178 ,  G01N33/5044 ,  G01N33/5067 ,  G01N33/5088 ,  G01N33/57415 ,  G01N33/57438 ,  G01N2500/00 ,  G01N2800/50 ,  G01N2800/52

    摘要： In some aspects, the invention provides a genetically tractable in situ non-human animal model for hepatocellular carcinoma. The model is useful, inter alia, in understanding the molecular mechanisms of liver cancer, in understanding the genetic alterations that lead to chemoresistance or poor prognosis, and in identifying and evaluating new therapies against hepatocellular carcinomas. The liver cancer model of this invention is made by altering hepatocytes to increase oncogene expression, to reduce tumor suppressor gene expression or both and by transplanting the resulting hepatocytes into a recipient non-human animal.The present invention also provides methods for identifying and validating tumor suppressor genes by screening pools of shRNAs that target genomic regions deleted in human cancers, such as human hepatocellular carcinomas. The present invention also provides validated tumor suppressor genes, and methods of inhibiting cell proliferation and/or tumor growth, for example by expression of such tumor suppressor genes.

    摘要翻译： 在一些方面，本发明提供了用于肝细胞癌的遗传易处的非人动物模型。 该模型除其他外，有助于理解肝癌的分子机制，了解导致化学耐药性或预后不良的遗传改变，以及鉴定和评估针对肝细胞癌的新疗法。 本发明的肝癌模型通过改变肝细胞以增加癌基因表达，减少肿瘤抑制基因表达或两者并通过将所得肝细胞移植到受体非人动物中来制备。 本发明还提供了通过筛选靶向人类癌症中缺失的基因组区域（例如人肝细胞癌）的shRNA的鉴定和验证肿瘤抑制基因的方法。 本发明还提供了经过验证的肿瘤抑制基因，以及例如通过表达这种肿瘤抑制基因来抑制细胞增殖和/或肿瘤生长的方法。

    Orthotopic, controllable, and genetically tractable non-human animal model for cancer
    4.
    发明申请
    Orthotopic, controllable, and genetically tractable non-human animal model for cancer 审中-公开
    原位，可控和可遗传的非人类动物模型

    公开(公告)号：US20090022685A1

    公开(公告)日：2009-01-22

    申请号：US11893611

    申请日：2007-08-15

    申请人： Scott W. Lowe ,  Gregory J. Hannon ,  Lars Zender ,  Wen Xue ,  Ross Dickins

    发明人： Scott W. Lowe ,  Gregory J. Hannon ,  Lars Zender ,  Wen Xue ,  Ross Dickins

    IPC分类号： A61K38/20 ,  A61K35/12 ,  A01K67/027 ,  G01N33/574 ,  A61P31/00 ,  C12Q1/02 ,  A61K31/7088 ,  A61K31/7105

    CPC分类号： A01K67/0271 ,  A01K2267/0331 ,  C07K14/82 ,  C12N15/1135 ,  C12N2310/111 ,  C12N2310/14 ,  C12N2310/53 ,  C12N2320/50 ,  C12N2799/027 ,  C12N2830/006

    摘要： This invention provides a genetically tractable in situ non-human animal model for hepatocellular carcinoma. The model is useful, inter alia, in understanding the molecular mechanisms of liver cancer, in understanding the genetic alterations (e.g., in oncogenes and tumor suppressor genes) that lead to chemoresistance or poor prognosis, and in identifying and evaluating new therapies against hepatocellular carcinomas. The liver cancer model of this invention is made by altering hepatocytes to increase oncogene expression, to reduce tumor suppressor gene expression or both, preferably by inducible, reversible, and/or tissue specific expression of double-stranded RNA molecules that interfere with the expression of a target gene, and by transplanting the resulting hepatocytes into a recipient non-human animal. The invention further provides a method to treat cancer involving cooperative interactions between a tumor cell senescence program and the innate immune system.

    摘要翻译： 本发明提供了用于肝细胞癌的遗传易处理的非人动物模型。 该模型特别有助于了解肝癌的分子机制，了解导致化疗耐药性或预后不良的遗传改变（例如，致癌基因和肿瘤抑制基因），以及鉴定和评估针对肝细胞癌的新疗法 。 本发明的肝癌模型通过改变肝细胞以增加癌基因表达，减少肿瘤抑制基因表达或两者，优选通过诱导的，可逆的和/或组织特异性表达的双链RNA分子来制备，所述双链RNA分子干扰表达 靶基因，并将所得肝细胞移植到受体非人动物中。 本发明还提供了一种治疗涉及肿瘤细胞衰老程序与先天免疫系统之间协同作用的癌症的方法。

    Orthotopic and genetically tractable non-human animal model for liver cancer and the uses thereof
    6.
    发明授权
    Orthotopic and genetically tractable non-human animal model for liver cancer and the uses thereof 有权
    肝癌的原位和遗传易感性非人动物模型及其用途

    公开(公告)号：US08137907B2

    公开(公告)日：2012-03-20

    申请号：US12072115

    申请日：2008-02-21

    申请人： Lars Zender ,  Scott W. Lowe ,  Mona S. Spector

    发明人： Lars Zender ,  Scott W. Lowe ,  Mona S. Spector

    IPC分类号： C12Q1/68 ,  C07H21/04 ,  C07K16/00 ,  C12P19/34

    CPC分类号： A01K67/0271 ,  A01K2217/058 ,  A01K2267/0331 ,  C07K14/4747 ,  C12N15/8509 ,  C12N2510/04 ,  C12N2517/02 ,  C12N2799/027 ,  G01N33/5067 ,  G01N33/57438 ,  G01N2500/00 ,  G01N2800/52

    摘要： This invention provides a genetically tractable in situ non-human animal model for hepatocellular carcinoma. The model is useful, inter alia, in understanding the molecular mechanisms of liver cancer, in understanding the genetic alterations that lead to chemoresistance or poor prognosis, and in identifying and evaluating new therapies against hepatocellular carcinomas. The liver cancer model of this invention is made by altering hepatocytes to increase oncogene expression, to reduce tumor suppressor gene expression or both and by transplanting the resulting hepatocytes into a recipient non-human animal.This invention also relates to the use of RNA interference (RNAi) technology in vivo to efficiently identify genes associated with liver cancer, in particular those encoding tumor suppressors, by knocking out candidate genes using RNAi and observing whether tumors would develop.

    摘要翻译： 本发明提供了用于肝细胞癌的遗传易处理的非人动物模型。 该模型除其他外，有助于理解肝癌的分子机制，了解导致化学耐药性或预后不良的遗传改变，以及鉴定和评估针对肝细胞癌的新疗法。 本发明的肝癌模型通过改变肝细胞以增加癌基因表达，减少肿瘤抑制基因表达或两者并通过将所得肝细胞移植到受体非人动物中来制备。 本发明还涉及RNA干扰（RNAi）技术在体内有效地鉴定与肝癌相关的基因，特别是编码肿瘤抑制因子的基因，通过使用RNAi敲除候选基因并观察肿瘤是否会发展。

    METHODS FOR TREATING FIBROSIS BY MODULATING CELLULAR SENESCENCE
    7.
    发明申请
    METHODS FOR TREATING FIBROSIS BY MODULATING CELLULAR SENESCENCE 审中-公开
    通过调节细胞感觉治疗纤维化的方法

    公开(公告)号：US20100310504A1

    公开(公告)日：2010-12-09

    申请号：US12679835

    申请日：2008-09-25

    申请人： Scott W. Lowe ,  Valery Krizhanovsky ,  Lars Zender

    发明人： Scott W. Lowe ,  Valery Krizhanovsky ,  Lars Zender

    IPC分类号： A61K38/20 ,  A61K38/21 ,  A61K38/18 ,  A61K35/12 ,  A61K31/7052 ,  A61K39/395 ,  C12Q1/02 ,  A61P1/16

    CPC分类号： A61K38/18 ,  A61K35/17 ,  A61K38/1774 ,  A61K38/19 ,  G01N33/5061 ,  G01N2510/00 ,  Y02A50/465

    摘要： Fibrosis arises as part of a wound healing response that maintains organ integrity following catastrophic tissue damage, but can also contribute to a variety of human pathologies, including liver cirrhosis. The invention demonstrates that cellular senescence acts to limit the fibrogenic response to tissue damage, thereby establishing a role for the senescence program in pathophysiological settings beyond cancer. Accordingly, the methods of the invention relate to modulating cellular senescence in disease tissue that have elevated numbers of senescent cells, such as in fibrotic tissues.

    摘要翻译： 纤维化是伤口愈合反应的一部分，其在灾难性组织损伤后维持器官完整性，但也可能导致多种人类病理，包括肝硬化。 本发明证明细胞衰老起限制对组织损伤的纤维形成反应，从而在衰老程序在癌症以外的病理生理环境中建立起一种作用。 因此，本发明的方法涉及调节具有升高的衰老细胞数量的疾病组织中的细胞衰老，例如在纤维组织中。

    Orthotopic and genetically tractable non-human animal model for liver cancer and the uses thereof
    9.
    发明申请
    Orthotopic and genetically tractable non-human animal model for liver cancer and the uses thereof 有权
    肝癌的原位和遗传易感性非人动物模型及其用途

    公开(公告)号：US20090029872A1

    公开(公告)日：2009-01-29

    申请号：US12072115

    申请日：2008-02-21

    申请人： Lars Zender ,  Scott W. Lowe ,  Mona S. Spector

    发明人： Lars Zender ,  Scott W. Lowe ,  Mona S. Spector

    IPC分类号： C40B30/06 ,  C07H21/00 ,  C12Q1/68

    CPC分类号： A01K67/0271 ,  A01K2217/058 ,  A01K2267/0331 ,  C07K14/4747 ,  C12N15/8509 ,  C12N2510/04 ,  C12N2517/02 ,  C12N2799/027 ,  G01N33/5067 ,  G01N33/57438 ,  G01N2500/00 ,  G01N2800/52

    摘要： This invention provides a genetically tractable in situ non-human animal model for hepatocellular carcinoma. The model is useful, inter alia, in understanding the molecular mechanisms of liver cancer, in understanding the genetic alterations that lead to chemoresistance or poor prognosis, and in identifying and evaluating new therapies against hepatocellular carcinomas. The liver cancer model of this invention is made by altering hepatocytes to increase oncogene expression, to reduce tumor suppressor gene expression or both and by transplanting the resulting hepatocytes into a recipient non-human animal.This invention also relates to the use of RNA interference (RNAi) technology in vivo to efficiently identify genes associated with liver cancer, in particular those encoding tumor suppressors, by knocking out candidate genes using RNAi and observing whether tumors would develop.

    摘要翻译： 本发明提供了用于肝细胞癌的遗传易处理的非人动物模型。 该模型除其他外，有助于理解肝癌的分子机制，了解导致化学耐药性或预后不良的遗传改变，以及鉴定和评估针对肝细胞癌的新疗法。 本发明的肝癌模型通过改变肝细胞以增加癌基因表达，减少肿瘤抑制基因表达或两者并通过将所得肝细胞移植到受体非人动物中来制备。 本发明还涉及RNA干扰（RNAi）技术在体内有效地鉴定与肝癌相关的基因，特别是编码肿瘤抑制因子的基因，通过使用RNAi敲除候选基因并观察肿瘤是否会发展。

    High throughput methods for functionally determining RNA interference efficiency
    10.
    发明授权
    High throughput methods for functionally determining RNA interference efficiency 有权
    用于功能测定RNA干扰效率的高通量方法

    公开(公告)号：US08901288B2

    公开(公告)日：2014-12-02

    申请号：US12739382

    申请日：2008-10-24

    申请人： Christof Fellmann ,  Scott W. Lowe ,  Gregory J. Hannon ,  Johannes E. Zuber

    发明人： Christof Fellmann ,  Scott W. Lowe ,  Gregory J. Hannon ,  Johannes E. Zuber

    IPC分类号： C07H21/00 ,  C12Q1/68 ,  C12N15/10

    CPC分类号： C12Q1/6897 ,  C12N15/1086 ,  C12N15/113 ,  C12N15/85 ,  C12N2310/14

    摘要： Provided is a single construct combining a sequence encoding an RNAi molecule, a sequence encoding a reporter, and a target sequence specific for the RNAi molecule. The construct can be used to determine the potency of the encoded RNAi molecule in a direct and unbiased way. These results can be used to inform the design of potent RNAi molecules of various types and can be extended to several other applications, including: (1) generation of tiled libraries comprising every possible RNAi molecule-encoding sequence for a given gene target; (2) large-scale parallel validation of RNAi molecules targeting many genes to generate validated RNAi molecule-encoding libraries; (3) experimental comparison of design algorithms and strategies; and (4) investigation of RNAi biology in target site mutagenesis assays by screening pools containing single nucleotide changes in target sites and/or in the RNAi molecule to identify the most relevant sequence characteristics of potent RNAi-target site predictions.

    摘要翻译： 提供了组合编码RNAi分子的序列，编码报道分子的序列和对RNAi分子特异的靶序列的单一构建体。 该构建体可以用于以直接和公正的方式确定编码的RNAi分子的效力。 这些结果可用于通知各种有效的RNAi分子的设计，并可扩展到其他几个应用，包括：（1）生成包含给定基因靶标的每个可能的RNAi分子编码序列的平铺文库; （2）针对许多基因的RNAi分子的大规模并行验证以产生经验证的RNAi分子编码文库; （3）设计算法和策略的实验比较; 和（4）通过在靶位点和/或RNAi分子中含有单核苷酸变化的筛选池来检测靶位点诱变测定中的RNAi生物学，以鉴定有效的RNAi靶位点预测的最相关的序列特征。