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1. 发明申请

US20110099644A1 MIG-6 KNOCKOUT MICE AND ELUCIDATION OF ASSOCIATION OF MIG-6 WITH EARLY ONSET DEGENERATIVE JOINT DISEASE AND ROLE AS A TUMOR SUPPRESSOR 有权
标题翻译： MIG-6 KNOCKOUT MICE和MIG-6与早期ONSET降解性联合病变和作为肿瘤抑制剂的作用的关联
公开(公告)号：US20110099644A1
公开(公告)日：2011-04-28
申请号：US11917557
申请日：2006-06-15
申请人： Yu-Wen Zhang , George F. Vande Woude
发明人： Yu-Wen Zhang , George F. Vande Woude
IPC分类号： G01N33/00 , A01K67/027 , C12N5/10 , C07H21/04 , C12N15/63 , C12N15/873 , C12Q1/68 , C40B30/04
CPC分类号： C12Q1/686 , A01K67/0276 , A01K2217/075 , A01K2227/105 , A01K2267/03 , A01K2267/0368 , C12N15/8509 , C12N2517/02 , C12N2800/30
摘要： The molecular mechanism underlying degenerative joint disease, also known as osteoarthritis (OA), is not fully understood. Disruption of mitogen inducible gene 6 (Mig-6) in mice by homologous recombination (KO mice) led to early onset OA as revealed by simultaneous enlargement and deformity of multiple joints, degradation of articular cartilage and the development of bony outgrowths or osteophytes within the joint space. The latter appeared to be derived from proliferation of mesenchymal progenitor cells followed by differentiation into chondrocytes. Because of the striking similarity to human OA, Mig-6 KO mice are a useful animal model for studying the mechanism of this disease and for testing new drugs or therapies for treating OA. These KO mice also developed epithelial hyperplasia, adenoma, and adenocarcinoma in organs such as lung, gallbladder, and bile duct. Mig-6 is therefore a tumor suppressor gene and is a candidate gene for the frequent Ip36 genetic alterations found in lung cancer. It can be used as a tumor biomarker as well as a target for cancer therapy. Mig-6 is located in human chromosome Ip36, a locus frequently associated with human lung cancer. Mig-6 is a negative regulator of EGF signaling, and like EGF, was induced by HGF/SF in human lung cancer cell lines. Frequently the receptors EGFR and Met were co-expressed, and Mig-6 was induced by both EGF and HGF/SF in a MAPK-dependent fashion. Not all tumor lines express Mig-6 in response to either EGF or HGF/SF. In these cases, missense and nonsense mutations in the Mig-6 coding region were found, as was evidence for Mig-6 transcriptional silencing.
摘要翻译：退行性关节病（也称为骨关节炎（OA））的分子机制尚未完全了解。通过同源重组（KO小鼠）破坏小鼠中的促分裂原诱导基因6（Mig-6）导致早期发作OA，其通过多个关节的同时扩大和畸形显示，关节软骨的降解以及骨内生长或骨赘的发育联合空间。后者似乎源自间充质祖细胞的增殖，然后分化成软骨细胞。由于与人OA的惊人相似，Mig-6 KO小鼠是研究这种疾病机制和检测新药物或治疗OA疗法的有用动物模型。这些KO小鼠也在器官如肺，胆囊和胆管中发展出上皮增生，腺瘤和腺癌。因此，Mig-6是一种肿瘤抑制基因，是肺癌发生频繁Ip36遗传改变的候选基因。它可以用作肿瘤生物标志物，也可以用作癌症治疗的靶标。 Mig-6位于人类染色体Ip36，这是经常与人类肺癌相关的基因座。 Mig-6是人肺癌细胞系中HGF / SF诱导的EGF信号传导的负调节因子，如EGF。 EGFR和Met共同受体共同表达，并且MAPK依赖型EGF和HGF / SF诱导Mig-6。不是所有的肿瘤细胞系都响应于EGF或HGF / SF表达Mig-6。在这些情况下，发现Mig-6编码区的错义和无义突变，Mig-6转录沉默的证据也是如此。

2. 发明申请

US20070020234A1 Inhibition of tumor angiogenesis by combination of thrombospondin-1 and inhibitors of vascular endothelial growth factor 审中-公开
标题翻译：通过血小板反应蛋白-1和血管内皮生长因子抑制剂的组合抑制肿瘤血管发生
公开(公告)号：US20070020234A1
公开(公告)日：2007-01-25
申请号：US10563616
申请日：2004-07-07
申请人： George Vande Woude , Yu-Wen Zhang
发明人： George Vande Woude , Yu-Wen Zhang
IPC分类号： A61K38/21 , A61K48/00 , A61K38/17 , A61K39/395
CPC分类号： A61K45/06 , A61K31/166 , A61K31/352 , A61K38/179 , A61K38/212 , A61K38/215 , A61K38/39 , A61K38/484 , A61K38/4886 , A61K2300/00
摘要： Hepatocyte growth factor/scatter factor (HGF/SF), acting through the Met receptor, plays an important role in most human solid tumors and inappropriate expression of this ligand-receptor pair is often associated with poor prognosis. The molecular basis for the malignant activity imparted by signaling of HGF/SF-Met in cancer cells has been attributed to its mitogenic and invasive properties. However, HGF/SF also induces angiogenesis, but the signaling mechanism has not been understood, nor has this activity been directly associated with HGF/SF-Met mediated tumorigenesis. HGF/SF induces expression in vitro of VEGF, a key agonist of tumor angiogenesis. By contrast, thrombospondin-1 (TSP-1) is a negative regulator of angiogenesis. This application discloses that, in the very same tumor cells, in addition to inducing VEGF expression, HGF/SF dramatically down regulates TSP-1 expression. TSP shut off plays an important, extrinsic role in HGF/SF-mediated tumor development, as ectopic expression of TSP-1 markedly inhibited tumor formation through the suppression of angiogenesis. While VEGF induced expression is sensitive to inhibitors of several pathways, including MAP kinase, PI3 kinase and Stat3, TSP-1 shut off by HGF/SF is prevented solely by inhibiting MAP kinase activation. Thus HGF/SF is a “switch” for turning on angiogenesis. TSP-1 is a useful antagonist to tumor angiogenesis, and therefore TSP-1 and agonist peptides and mimics, as well as inducers of TSP-1, have therapeutic value when used in conjunction with inhibitors of VEGF.
摘要翻译：通过Met受体起作用的肝细胞生长因子/分散因子（HGF / SF）在大多数人类实体瘤中起重要作用，并且该配体 - 受体对的不适当表达通常与预后不良相关。通过HGF / SF-Met在癌细胞中的信号转导所产生的恶性活性的分子基础已经归因于其有丝分裂和侵入性质。然而，HGF / SF也诱导血管发生，但是尚未了解信号机制，也没有这种活性与HGF / SF-Met介导的肿瘤发生直接相关。 HGF / SF诱导体外VEGF表达，VEGF是肿瘤血管发生的关键激动剂。相比之下，血小板反应蛋白-1（TSP-1）是血管生成的负调节因子。该申请公开了在相同的肿瘤细胞中，除诱导VEGF表达外，HGF / SF显着下调TSP-1表达。 TSP关闭在HGF / SF介导的肿瘤发展中起着重要的外在作用，因为TSP-1的异位表达通过抑制血管生成显着抑制肿瘤形成。虽然VEGF诱导的表达对几种途径的抑制剂（包括MAP激酶，PI3激酶和Stat3）敏感，但HGF / SF阻断的TSP-1仅通过抑制MAP激酶活化来防止。因此，HGF / SF是开启血管生成的“开关”。 TSP-1是肿瘤血管生成的有用拮抗剂，因此TSP-1和激动剂肽和模拟物以及TSP-1的诱导剂在与VEGF抑制剂结合使用时具有治疗价值。

3. 发明申请

US20080196110A1 Immune-Compromised Transgenic Mice Expressing Human Hepatocyte Growth Factor (Hhgf) 有权
标题翻译：表达人类肝细胞生长因子（hHGF）的免疫缺陷型转基因小鼠
公开(公告)号：US20080196110A1
公开(公告)日：2008-08-14
申请号：US11571947
申请日：2005-07-12
申请人： George F. Vande Woude , Yu-wen Zhang , Nariyoshi Shinomiya
发明人： George F. Vande Woude , Yu-wen Zhang , Nariyoshi Shinomiya
IPC分类号： G01N33/53 , A01K67/027 , C12N15/00 , C12P21/00 , C12N5/06
CPC分类号： A01K67/0271 , A01K67/0275 , A01K2217/052 , A01K2217/15 , A01K2217/203 , A01K2217/206 , A01K2227/105 , A01K2267/01 , A01K2267/0331 , C07K14/4753 , C12N15/8509
摘要： A transgenic animal model for evaluating growth, survival and/or metastasis of xenotransplanted normal or tumor cells or tissue is disclosed, in which a human growth factor, hHGF stimulates growth in vivo of human cells or tissue. A strain of Tg mice on the C3H background that is immunocompromised as a result of a homozygous scid gene has been bred which express a nucleic acid encoding hHGF/SE The ectopically expressed hHGF/SF ligand significantly enhances growth of human tumor cell lines and explanted tumor cells or tissue that express the Met receptor for hHGF. Such animals also have an enlarged normal livers and greater than normal liver regenerative capacity. Any Met-expressing hHGF-dependent human cells, including hepatocytes and various stem cells can survive and grow in such animals.
摘要翻译：公开了用于评估异种移植的正常或肿瘤细胞或组织的生长，存活和/或转移的转基因动物模型，其中人生长因子hHGF刺激人细胞或组织的体内生长。已经培育了作为纯合scid基因的免疫受损的C3H背景上的Tg小鼠的菌株，其表达编码hHGF / SE的核酸。异位表达的hHGF / SF配体显着增强人肿瘤细胞系和外植体肿瘤的生长表达hHGF的Met受体的细胞或组织。这样的动物也具有扩大的正常肝脏并且大于正常的肝脏再生能力。任何Met表达的hHGF依赖性人细胞，包括肝细胞和各种干细胞都可以在这样的动物中存活和生长。

4. 发明授权

US08466339B2 Mig-6 knockout mice and elucidation of association of Mig-6 with early onset degenerative joint disease and role as a tumor suppressor 有权
标题翻译： Mig-6敲除小鼠，并阐明Mig-6与早发性退行性关节病的关联以及作为肿瘤抑制因子的作用
公开(公告)号：US08466339B2
公开(公告)日：2013-06-18
申请号：US11917557
申请日：2006-06-15
申请人： Yu-Wen Zhang , George F. Vande Woude
发明人： Yu-Wen Zhang , George F. Vande Woude
IPC分类号： A01K67/027 , A01K67/00 , A01K67/033 , G01N33/00
CPC分类号： C12Q1/686 , A01K67/0276 , A01K2217/075 , A01K2227/105 , A01K2267/03 , A01K2267/0368 , C12N15/8509 , C12N2517/02 , C12N2800/30
摘要： Disruption of mitogen inducible gene 6 (Mig-6) in mice by homologous recombination (KO mice) led to early onset osteoarthritis (OA) as revealed by simultaneous enlargement and deformity of multiple joints, degradation of articular cartilage and the development of bony outgrowths or osteophytes within the joint space. Because of the striking similarity to human OA, Mig-6 KO mice are a useful animal model for studying the mechanism of this disease and for testing new drugs or therapies for treating OA. These KO mice also developed epithelial hyperplasia, adenoma, and adenocarcinoma in organs such as lung, gallbladder, and bile duct. Mig-6 is therefore a tumor suppressor gene and is a candidate gene for the frequent Ip36 genetic alterations found in lung cancer. It can be used as a tumor biomarker as well as a target for cancer therapy.
摘要翻译：通过同源重组（KO小鼠）破坏小鼠中的促分裂原诱导基因6（Mig-6）导致早发性骨关节炎（OA），如通过多关节的同时扩大和畸形显示的，关节软骨的退化和骨质生长的发展或骨赘在联合空间内。由于与人OA的惊人相似，Mig-6 KO小鼠是研究这种疾病机制和检测新药物或治疗OA疗法的有用动物模型。这些KO小鼠也在器官如肺，胆囊和胆管中发展出上皮增生，腺瘤和腺癌。因此，Mig-6是一种肿瘤抑制基因，是肺癌发生频繁Ip36遗传改变的候选基因。它可以用作肿瘤生物标志物，也可以用作癌症治疗的靶标。

5. 发明授权

US07968762B2 Immune-compromised transgenic mice expressing human hepatocyte growth factor (hHGF) 有权
标题翻译：表达人肝细胞生长因子（hHGF）的免疫受损转基因小鼠
公开(公告)号：US07968762B2
公开(公告)日：2011-06-28
申请号：US11571947
申请日：2005-07-12
申请人： George F. Vande Woude , Yu-wen Zhang , Nariyoshi Shinomiya
发明人： George F. Vande Woude , Yu-wen Zhang , Nariyoshi Shinomiya
IPC分类号： A01K67/027 , A01K67/00 , A01K67/033 , G01N33/00 , C12N15/00
CPC分类号： A01K67/0271 , A01K67/0275 , A01K2217/052 , A01K2217/15 , A01K2217/203 , A01K2217/206 , A01K2227/105 , A01K2267/01 , A01K2267/0331 , C07K14/4753 , C12N15/8509
摘要： A transgenic animal model for evaluating growth, survival and/or metastasis of xenotransplanted normal or tumor cells or tissue is disclosed, in which a human growth factor, hHGF stimulates growth in vivo of human cells or tissue. A strain of Tg mice on the C3H background that is immunocompromised as a result of a homozygous scid gene has been bred which express a nucleic acid encoding hHGF/SE The ectopically expressed hHGF/SF ligand significantly enhances growth of human tumor cell lines and explanted tumor cells or tissue that express the Met receptor for hHGF. Such animals also have an enlarged normal livers and greater than normal liver regenerative capacity. Any Met-expressing hHGF-dependent human cells, including hepatocytes and various stem cells can survive and grow in such animals.
摘要翻译：公开了用于评估异种移植的正常或肿瘤细胞或组织的生长，存活和/或转移的转基因动物模型，其中人生长因子hHGF刺激人细胞或组织的体内生长。已经培育了作为纯合scid基因的免疫受损的C3H背景上的Tg小鼠的菌株，其表达编码hHGF / SE的核酸。异位表达的hHGF / SF配体显着增强人肿瘤细胞系和外植体肿瘤的生长表达hHGF的Met受体的细胞或组织。这样的动物也具有扩大的正常肝脏并且大于正常的肝脏再生能力。任何Met表达的hHGF依赖性人细胞，包括肝细胞和各种干细胞都可以在这样的动物中存活和生长。

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