Study of Progenitor Regulation in Mouse Mammary Gland

描述(由申请人提供)：拟议的发育生物学和肿瘤学培训将为毕比教授提供生物学知识和技能的基础(近期目标)，使他能够开发一个全面的多学科癌症研究计划，充分利用细胞/技术接口来探索与理解肿瘤发展的生物学相关的基本问题(长期目标)。在McArdle癌症研究实验室的Caroline Alexander教授的指导下，职业发展计划整合了教学培训、实验室技能和实践研究。这项研究旨在了解乳腺中祖细胞比例的调节。最近出现了一种具有祖细胞特征(包括BrDu保留、ABC转运蛋白表达和形态/位置)的乳腺细胞的描述。与大多数乳腺上皮细胞不同，这些长寿的祖细胞可以在悬浮(乳房)中繁殖，并在提供适当的球茎后分化为两个乳腺谱系。Alexander博士的实验室发现，作为对Wnt致癌途径的响应，小鼠乳腺中的祖细胞比例失调，并伴随着体内癌前病变的发展。在这项拟议的研究中，毕比博士将利用神经和造血祖细胞研究得出的信息，测试乳腺中的祖细胞比例通常是否受到其他成熟阶段细胞分泌的因素的积极调控。这一假设很难用传统的文化模型来解释。为了测试生长调节细胞的相互作用，祖细胞(来自乳房)将与分化的细胞混合。微尺度工程促进了对可溶性效应物(无细胞接触)以及细胞相关效应物(接触细胞)重要性的研究。这类研究的结果将表明，祖细胞是否受到乳腺上皮中其他类型细胞的生长调节，从而更全面地了解乳腺癌的发展机制。也有可能的是，更好的理解与新的文化构建相结合将导致一种支持男性导管形态发生的培养模式。这样的模型将对乳腺癌研究产生重大影响。

DESCRIPTION (provided by applicant): The proposed training in developmental biology and oncology will provide Prof. Beebe with a foundation of biological knowledge and skills (immediate goal) allowing him to develop a comprehensive multidisciplinary cancer research program that fully leverages the cellular/technology interface to explore basic questions pertinent to understanding the biology of tumor development (long term goal). The career development plan integrates didactic training, laboratory skills, and hands-on research under the guidance of Prof. Caroline Alexander of the McArdle Laboratory for Cancer Research. The research is aimed at understanding the regulation of the progenitor fraction in the mammary gland. Recently a description of mammary cells with progenitor characteristics (including BrDu retention, expression of ABC transporter, and morphology/position) has emerged. Unlike the majority of mammary epithelial cells, these long-lived progenitors can be propagated in suspension (mammospheres) and differentiate into both mammary lineages with the provision of appropriate stiumuli. Dr. Alexander's lab has found that in response to the Wnt oncogenic pathway, the progenitor fraction in mouse mammary gland is dysregulated, and this is accompanied by the development of preneoplastic hyperplasia in vivo. In the proposed research, Dr. Beebe will use the information derived from the study of neural and hematopoietic progenitor cells, to test whether the progenitor fraction in the mammary gland is normally actively regulated by factors secreted by cells at other stages of maturation. This hypothesis is not easy to address using traditional culture models. In order to test for growth-regulating cell interactions, progenitor cells (from mammospheres) will be mixed with differentiated cells. Micro scale engineering facilitates studies examining the importance of soluble effectors (no cell contact) as well as cell-associated effectors (cells in contact). The results of such studies will show whether the progenitor compartment is subject to growth regulation by other cell types in the mammary epithelium leading to a more complete understanding of the mechanisms of cancer development in the mammary gland. It is also possible that an improved understanding combined with new culture constructs will lead to a culture model that can support mannary ductal morphagenesis. Such a model would have a significant impact on breast cancer research.