The role of MEKK1-dependent gene expression in tumor progression

MEKK1依赖性基因表达在肿瘤进展中的作用

基本信息

批准号：
7666286
负责人：
Bruce D Cuevas
金额：
$ 15.04万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-16 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7666286
关键词：
Address Animal Model Animals Area Basement membrane Bioinformatics Biological Assay Biology Biomedical Research Breast Adenocarcinoma Breast Carcinoma Cancer Center Candidate Disease Gene Cell Line Cell Proliferation Cell physiology Cells Cellular biology Cessation of life Commit Conditioned Culture Media Core Facility Development Environment Faculty Fibroblasts Gelatinase B Gene Expression Gene Targeting Genes Genetic Genetic Screening Genetic Transcription Goals Growth Home environment Human IL8 gene Image In Vitro Laboratories Life Light MAP Kinase Gene MAP3K1 gene MAPK14 gene MAPK8 gene Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Mammary gland Matrix Metalloproteinases Mediating Mentors Methods Mitogen-Activated Protein Kinase Inhibitor Modeling Mus Mutation Neoplasm Metastasis Oncogenes Organ Organ Specificity Pathway interactions Peptide Hydrolases Phenotype Phosphotransferases Platelet-Derived Growth Factor Polyomavirus Population Primary Neoplasm Regulation Relative (related person)Research Research Personnel Research Project Grants Reverse Transcriptase Polymerase Chain Reaction Role Series Signal Transduction Small Interfering RNA Solid Neoplasm Staging Stromal Cell-Derived Factor 1 Stromal Neoplasm Stromelysin 1 System Technology Testing Therapeutic Intervention Time Tissue Inhibitor of Metalloproteinase-1 Tissue Inhibitor of Metalloproteinase-3 Tissues Training Transcription Factor AP-1 Transgenic Mice Tumor Cell Invasion Tumor Cell Line Validation Vascular Endothelial Growth Factors Viral Tumor Antigens Xenograft procedure angiogenesis base career cell motility cell stroma cell type cellular imaging collagenase 3 computing resources experience fos-related antigen-2 gene function in vitro Assay in vivo knock-down luminescence migration mouse model neoplastic cell response sialosyl-T antigen small hairpin RNA tumor tumor growth tumor progression tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): My career plans are in academic biomedical research. I have received broad training in the characterization of kinase signaling and function. However, a major focus of my independent research will be the identification of genetic changes mediated by signaling networks; this requires new areas of expertise in array-based genetic screens and animal models to identify potential targets for therapeutic intervention. Gary Johnson is an excellent choice as my mentor in light of his experience in training researchers and his proven ability to address important questions of signaling function in cell biology. My co-mentors Drs. Van Dyke and Perou are also committed to my training and have considerable experience in approaches and methods required in my research. The UNC Lineberger Cancer Center is home to CORE facilities that will provide support throughout the research project. Thus UNC provides an outstanding scientific environment that also includes interaction with senior faculty and participation in seminar series. The goal of this project is to define the role of MEKK1 signaling in the regulation of tumor progression. MEKK1 regulates gene expression by controlling AP-1 transcription factor activity, expression and stability. In a transgenic mouse model that develops metastatic mammary adenocarcinoma, MEKK1-deficient transgenic mice show delayed formation of metastases compared to control littermates. The hypothesis is that MEKK1 regulates tumor progression through multiple mechanisms. The proposed studies will determine the impact of MEKK1 on gene expression required for tumor progression. MEKK1-dependent genes will be identified by using gene array analysis to compare MEKK1-deficient cells to those that express MEKK1. Expression of these genes will be blocked in invasive breast carcinoma cells to verify that these genes regulate tumor functions required for metastasis. Live tumor imaging will be used to validate the function of these genes on the course of tumor cell metastasis in vivo. In addition, I will examine the role of previously identified MEKK1-dependent genes in the biology of breast tumor cells and non-tumor stroma. Relevance: The majority of cancer deaths are due to the formation of secondary tumors called metastasis. Greater understanding of metastasis-related mechanisms and genetics is necessary to develop new anti-metastasis therapies. MEKK1 is a gene that regulates tumor metastasis, and these studies will define how this occurs.

描述（由申请人提供）：我的职业计划是学术生物医学研究。我接受了激酶信号传导和功能表征方面的广泛培训。然而，我独立研究的一个主要重点将是识别信号网络介导的遗传变化；这需要基于阵列的遗传筛查和动物模型方面的新专业知识领域，以确定治疗干预的潜在目标。加里·约翰逊（Gary Johnson）是我的导师的绝佳选择，因为他在培训研究人员方面拥有丰富的经验，而且他在解决细胞生物学信号功能重要问题方面的能力已得到证实。我的共同导师博士。范戴克和佩鲁也致力于我的培训，并且在我的研究所需的方法和方法方面拥有丰富的经验。北卡罗来纳大学莱恩伯格癌症中心拥有核心设施，将为整个研究项目提供支持。因此，北卡罗来纳大学提供了一个出色的科学环境，其中还包括与高级教师的互动和参加系列研讨会。该项目的目标是明确 MEKK1 信号传导在肿瘤进展调节中的作用。 MEKK1 通过控制 AP-1 转录因子的活性、表达和稳定性来调节基因表达。在发生转移性乳腺癌的转基因小鼠模型中，与对照同窝小鼠相比，MEKK1 缺陷的转基因小鼠显示出转移形成延迟。假设 MEKK1 通过多种机制调节肿瘤进展。拟议的研究将确定 MEKK1 对肿瘤进展所需基因表达的影响。通过使用基因阵列分析将 MEKK1 缺陷细胞与表达 MEKK1 的细胞进行比较来鉴定 MEKK1 依赖性基因。这些基因的表达将在侵袭性乳腺癌细胞中被阻断，以验证这些基因调节转移所需的肿瘤功能。活体肿瘤成像将用于验证这些基因在体内肿瘤细胞转移过程中的功能。此外，我将研究先前确定的 MEKK1 依赖性基因在乳腺肿瘤细胞和非肿瘤基质生物学中的作用。相关性：大多数癌症死亡是由于称为转移的继发性肿瘤的形成。开发新的抗转移疗法需要更好地了解转移相关机制和遗传学。 MEKK1 是一种调节肿瘤转移的基因，这些研究将确定这种情况是如何发生的。