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Molecular Regulation of Human Melanoma Metastasis

人类黑色素瘤转移的分子调控

基本信息

批准号：
7163708
负责人：
RAKESH K SINGH
金额：
$ 18.82万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-04-01 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7163708
关键词：
Address Affinity Amino Acids Angiogenic Factor Binding Biological Assay Blood capillaries CXC Chemokines CXCR Cell Proliferation Cells Collaborations Complement Critiques Cutaneous Melanoma Data Development Disease Endothelial Cells Event Experimental Models Family Gene Silencing Generations Growth Homologous Gene Human IL8RA gene IL8RB gene Immunoblotting Immunohistochemistry In Situ In Vitro Injection of therapeutic agent Interleukin 8A Receptor Interleukin-8 Interleukins Invasive Knock-out Knowledge Ligand Binding Lung Mediating Melanoma Cell Metastatic Lesion Molecular Mus Mutation Neoplasm Metastasis Nude Mice Numbers Object Attachment Pathogenesis Pathway Analysis Pathway interactions Pattern Phenotype Phospho-Specific Antibodies Play Primary Neoplasm Principal Investigator Progress Reports RNA Interference Reading Regulation Relative (related person)Research Design Research Institute Role Signal Pathway Signal Transduction Signal Transduction Pathway Small Interfering RNA Specimen Staining method Stains Statistically Significant System Testing Therapeutic Thick Time Transfection Tube Tumor Angiogenesis Viral Week Xenograft Model Xenograft procedure angiogenesis autocrine capillary cell growth cell transformation chemokine receptor design in vivo inhibitor/antagonist innovation insight melanocyte melanoma member migration neoplastic cell novel therapeutics paracrine programs receptor research study response small molecule subcutaneous therapeutic target tumor tumor growth vector

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this application is to determine the molecular mechanism(s) of interleukin (IL)-8 in malignant melanoma pathogenesis. IL-8, a member of the CXC chemokine family is constitutively expressed in malignant melanoma and functions as an autocrine/paracrine growth, invasive and angiogenic factor. The effect of IL-8 is mediated through two high affinity receptors, CXCR1 and CXCR2, expressed on melanoma cells as well as endothelial cells. Binding of IL-8 to CXCR1 and CXCR2 can initiate diverse cellular responses, however, the precise role of activation of CXCR1 and/or CXCR2 by IL-8 in malignant melanoma is not known. Therefore, the specific objective of this application is to determine the distinct functional role of CXCR1 and CXCR2 in mediating IL-8-induced cellular responses that regulate melanoma growth, invasion, angiogenesis, and metastasis. We hypothesize that interaction of IL-8 with CXCR1 and CXCR2 activates different downstream signaling pathways and plays a diverse role in melanoma growth, invasion, angiogenesis, and metastasis. We will test this hypothesis and accomplish the objective of this application by: 1) Determining whether activation of CXCR1 and/or CXCR2 by IL-8 result in distinct or overlapping roles in regulating cellular phenotypes associated with melanoma growth, invasion and metastasis; 2) Examining the diverse roles of CXCR1 and CXCR2 in endothelial cells in an IL-8-induced angiogenic response in melanoma; and 3) Identifying the signal transduction mechanism(s) involved in IL-8-induced CXCR1- and CXCR2-dependent modulation of melanoma cell growth, survival and invasive response. We will examine the CXCR1 and CXCR2-dependent IL-8-mediated effects in vitro and in vivo. We will use specific targeting of CXCR1 and/or CXCR2 in vivo using small molecule antagonists and adenoviral-siRNA vectors in xenograft models and mCXCR2 knockout nude mice. Using pathways specific inhibitors, phospho-specific antibodies, immunoblotting and immunohistochemistry, we will examine the downstream signaling pathways following CXCR1 and/or CXCR2 activation in vitro and in vivo. These studies will identify distinct and/or overlapping roles for CXCR1 and CXCR2 activation and their downstream signaling pathways in mediating IL-8-induced responses in malignant melanoma growth, angiogenesis, and metastasis. We anticipate that the knowledge gained from these studies will identify new therapeutic targets for inhibiting the ligand binding and/or signal transduction events and the development of therapeutics for malignant melanoma.

描述（由申请方提供）：本申请的长期目的是确定白细胞介素（IL）-8在恶性黑色素瘤发病机制中的分子机制。 IL-8是CXC趋化因子家族的成员，在恶性黑素瘤中组成性表达，并作为自分泌/旁分泌生长、侵袭和血管生成因子发挥作用。 IL-8的作用通过两种高亲和力受体CXCR 1和CXCR 2介导，这两种受体在黑素瘤细胞以及内皮细胞上表达。 IL-8与CXCR 1和CXCR 2的结合可引发多种细胞应答，然而，IL-8在恶性黑素瘤中激活CXCR 1和/或CXCR 2的确切作用尚不清楚。因此，本申请的具体目的是确定CXCR 1和CXCR 2在介导IL-8诱导的细胞应答中的不同功能作用，所述细胞应答调节黑素瘤生长、侵袭、血管生成和转移。我们假设IL-8与CXCR 1和CXCR 2的相互作用激活不同的下游信号通路，并在黑色素瘤生长、侵袭、血管生成和转移中发挥不同的作用。 1）确定IL-8对CXCR 1和/或CXCR 2的激活是否导致在调节与黑素瘤生长、侵袭和转移相关的细胞表型中的不同或重叠作用; 2）检查黑素瘤中IL-8诱导的血管生成应答中内皮细胞中CXCR 1和CXCR 2的不同作用;和3）鉴定参与IL-8诱导的CXCR 1和CXCR 2依赖性调节黑素瘤细胞生长、存活和侵袭性应答的信号转导机制。我们将在体外和体内研究CXCR 1和CXCR 2依赖性IL-8介导的作用。我们将在异种移植模型和mCXCR 2敲除裸鼠中使用小分子拮抗剂和腺病毒-siRNA载体在体内特异性靶向CXCR 1和/或CXCR 2。使用途径特异性抑制剂，磷酸化特异性抗体，免疫印迹和免疫组织化学，我们将检查CXCR 1和/或CXCR 2体外和体内激活后的下游信号通路。这些研究将确定CXCR 1和CXCR 2激活及其下游信号通路在介导IL-8诱导的恶性黑色素瘤生长、血管生成和转移反应中的不同和/或重叠作用。我们预计，从这些研究中获得的知识将确定新的治疗靶点，抑制配体结合和/或信号转导事件和恶性黑色素瘤的治疗方法的发展。