Paracrine TGF-Beta Signaling in Tumor Initiation and Progression

肿瘤发生和进展中的旁分泌 TGF-β 信号转导

• 批准号: 7289826
• 负责人: LYNN M MATRISIAN
• 金额: $ 149.21万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7289826
• 关键词: Paracrine; TGF; Beta; Signaling; Tumor

This proposal seeks to establish the Vanderbilt University Tumor Microenvironment Network (VUTMEN) to contribute to the generation of a comprehensive understanding of the role of the tumor stroma in cancer initiation, progression, and metastasis. The strategy used by the VUTMEN is to focus our efforts on understanding the downstream mechanisms used by a critical biological mediator of host:tumor interactions.TGFbeta. Project 1 uses sophisticated mouse genetics and advanced proteomic technologies to identify the downstream effectors of tumor and stromal TGF|3 signaling pathways that influence mammary gland tumorigenesis. Project 2 uses a combination of human prostate cancer and mouse model-derived cells and the tissue recombination model to examine the effectors of TGFp that modulate prostatic carcinogenesis. The role of TGFbeta in driving the vicious cycle that regulates the growth of breast metastases in bone is the topic of Project 3. All results will be followed up in human tumor samples. The VUTMEN supports 3 "Integrative Shared Resources" that bring state-of-the-art technologies and a systems biology approach to the three VUTMEN projects. The Protein Collection and Proteomics Core provides proteomic technologies specifically relevant to the tumor microenvironment, including microdialysis and imaging mass spectroscopy. The Image Fusion Core is devoted to novel imaging strategies that enhance the understanding of the tumor microenvironment, including a multi-parametric and multi-modality approach known as image fusion. The Biomathematics and Bioinformatics Core develops new approaches to analyzing complex data sets and generates mathematical models for iterative hypothesis generation and testing. We propose that the acknowledged complexity of the tumor microenvironment can be unraveled by the strategy of focusing our efforts on the key regulatory pathway of TGFbeta. This will be achieved through the systematic examination of known molecular modulators that are downstream of TGFbeta and the discovery of new ones using proteomic approaches, examining biological effects in vivo in real time and correlating the results with molecular parameters using genetic manipulation and image fusion technologies, using mathematical modeling to iteratively generate hypotheses and test them experimentally, and comparing the results in three distinct but related organ sites. Our goal is to generate a comprehensive understanding of the mechanisms used by TGFbeta to control the reciprocal interactions between a tumor and its microenvironment.

该建议旨在建立范德比尔特大学肿瘤微环境网络（VUTMEN） 有助于对肿瘤基质在癌症的作用的全面了解 启动，进展和转移。 Vutmen使用的策略是将我们的精力集中在 了解宿主关键生物介体使用的下游机制：肿瘤 Interactions.tgfbeta。项目1使用复杂的鼠标遗传学和先进的蛋白质组学技术 确定影响乳腺的肿瘤和基质TGF | 3信号通路的下游效应子 腺体肿瘤发生。项目2结合了人类前列腺癌和小鼠模型来源 细胞和组织重组模型，以检查调节前列腺的TGFP的效应子 致癌作用。 TGFBETA在驱动调节乳房转移生长的恶性循环中的作用 在骨骼中是项目3的主题。所有结果将在人类肿瘤样品中进行。 Vutmen 支持3个带来最先进技术和系统生物学的“综合共享资源” 三个Vutmen项目的方法。蛋白质收集和蛋白质组学核心提供蛋白质组学 与肿瘤微环境特别相关的技术，包括微透析和成像质量 光谱法。图像融合核心致力于新的成像策略，以增强 了解肿瘤微环境，包括多种合法性方法 称为图像融合。生物学和生物信息学核心开发了新的方法 分析复杂的数据集并生成数学模型，用于迭代假设生成和 测试。我们建议，可以揭示肿瘤微环境的公认复杂性 将我们的精力集中在TGFBETA的关键监管途径上的策略。这将通过 系统检查TGFBETA下游的已知分子调节剂和发现 使用蛋白质组学方法的新方法，实时检查体内的生物学作用并将 使用遗传操纵和图像融合技术与分子参数的结果，使用 数学建模与迭代产生假设并实验测试，并比较 导致三个不同但相关的器官位点。我们的目标是对 TGFBETA使用的机制来控制肿瘤与其之间的相互作用 微环境。