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

• 批准号: 7895607
• 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
• 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/7895607
• 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

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）：我的职业计划是在学术生物医学研究中。我接受了激酶信号传导和功能表征的广泛培训。但是，我独立研究的重点是确定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的新专业知识领域，以确定治疗干预的潜在目标。鉴于他在培训研究人员方面的经验以及解决细胞生物学信号功能的重要问题，加里·约翰逊（Gary Johnson）是我的导师的绝佳选择。我的联合官员。 Van Dyke和Perou也致力于我的培训，并且在我的研究中所需的方法和方法方面具有丰富的经验。 UNC Lineberger癌症中心是将在整个研究项目中提供支持的核心设施的所在地。因此，UNC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研讨会系列的互动。该项目的目的是定义MEKK1信号在调节肿瘤进展中的作用。 MEKK1通过控制AP-1转录因子活性，表达和稳定性来调节基因表达。在开发转移性乳腺腺癌的转基因小鼠模型中，MEKK1缺陷型转基因小鼠与对照双胞胎相比显示转移的形成延迟。假设是MEKK1通过多种机制调节肿瘤进展。拟议的研究将确定MEKK1对肿瘤进展所需的基因表达的影响。通过使用基因阵列分析将MEKK1缺陷型细胞与表达MEKK1的细胞进行比较，将鉴定MEKK1依赖性基因。这些基因的表达将在浸润性乳腺癌细胞中阻塞，以验证这些基因调节转移所需的肿瘤功能。活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，我将研究先前鉴定的MEKK1依赖性基因在乳腺肿瘤细胞和非肿瘤基质的生物学中的作用。相关性：大多数癌症死亡是由于形成了称为转移的继发性肿瘤。对转移相关的机制和遗传学的更多了解对于开发新的抗核治疗是必要的。 MEKK1是调节肿瘤转移的基因，这些研究将定义这种情况的发生。