Analysis of the cellular and molecular determinants of the human breast hierarchy

人类乳房层次结构的细胞和分子决定因素分析

基本信息

批准号：
9085334
负责人：
CHARLOTTE KUPERWASSER
金额：
$ 46.22万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-25 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9085334
关键词：
Adult Affect Alveolar Alveolus Architecture Back Biological Biological Assay Biological Models Biology Breast Breast Cancer cell line Breast Epithelial Cells Cell Count Cells Clinical Complex Development Differentiation and Growth Duct (organ) structure Ductal Elements Endocrine Epithelial Epithelial Cells Estrogens Event Fatty acid glycerol esters Fibroblast Growth Factor Fistula Goals Growth Health Hormonal Hormones Human Human Biology Immunocompromised Host In Vitro Laboratories Lactation Lead Lobule Location Malignant Neoplasms Mammaplasty Mammary Gland Parenchyma Mammary gland Maps Modeling Molecular Molecular Genetics Morphogenesis Multipotent Stem Cells Mus Myoepithelial cell Natural regeneration Papilloma Pathologic Pathway interactions Phenocopy Phenotype Population Pregnancy Progesterone Property Regulation Reporting Rodent Sampling Signal Pathway Signal Transduction Somatotropin Source Stem cells TACSTD1 gene Testing Tissues WNT Signaling Pathway WNT1 gene Work base in vitro Model in vivo in vivo Model innovation insight malignant breast neoplasm mammary epithelium meetings metaplastic cell transformation overexpression pregnant primitive cell progenitor regenerative reproductive response stem stem cell biology tool

项目摘要

DESCRIPTION (provided by applicant): The identification of human mammary progenitor cells and understanding their regulation is critical to enumerating the origins and events that control pathologic conditions. Determining the identity and activity of normal primitive cells could lead t a better understanding to the connection between stem cell biology and cancer. Our study is directed towards understanding the mechanisms that underlie human breast development and the regulation of primitive progenitor cells by hormone-growth factor signaling. The limited understanding of human breast development and stem cell biology has largely been due to the lack of appropriate model systems and assays to detect, analyze, and characterize stem cell properties. In recent years, our laboratory has developed and optimized various in vivo and in vitro tools to study the biology and mechanisms governing human breast development We have pioneered and implemented the use of an innovative in vivo model to study human mammary development by exploiting the mouse mammary fat pad of immunocompromised mice as a source of important endocrine signaling events and using grafted human stroma to support the growth and differentiation of the human mammary epithelium. In recent work, we have identified i) four distinguishable epithelial differentiation states (two luminal phenotypes and two basal phenotypes) within human breast tissues that differ on the basis of CD24, EpCAM and CD49f expression, ii) the existence of bipotent progenitors that contribute to structurally distinct elements (ducts and lobule/alveoli), iii) the hormonal combinations that enhance stem/progenitor cell activity within human epithelial cells, and iv) a hormone growth factor mechanism through TBX3 expression can regulate breast stem-like cells. In Aim 1 of this project, we will delineate the epithelial hierarchy in adult human breast tissue. In Aim 2, we will determine how hormone-growth factor signaling regulates human breast progenitor cell activity. Our studies provide innovative insight into the identity of human breast progenitor cells and provide critical molecula underpinnings by which hormones drive human breast progenitor cell morphogenesis that could serve as focal points during the development of pathological conditions.

描述（由申请人提供）：鉴定人类乳腺祖细胞及其调节对于列举控制病理状况的起源和事件至关重要。确定正常原始细胞的同一性和活性可能会更好地理解干细胞生物学与癌症之间的联系。我们的研究旨在了解人类乳房发育构成的机制以及通过激素增长因子信号传导对原始祖细胞的调节。对人乳房发育和干细胞生物学的理解有限，主要是由于缺乏适当的模型系统以及用于检测，分析和表征干细胞特性的测定法。近年来，我们的实验室已经开发并优化了各种体内和体外工具来研究人类乳房发展的生物学和机制，我们已经开创并实施了使用创新的体内模型来研究人类乳腺发展的创新性，通过利用人类乳腺的乳腺来促进人类的乳腺剂量，并促进了人类的跨性别范围，并促进了人类的跨性别范围，并构成了人类的跨性别范围，以促进人类的依据，以促进人类的依据，以实现人类的依据，以促进人类的依据，以促进人类的依据，以实现人类的依据，以促进人类的依据，以实现人类的依据，以促进人类的依据，以实现人类的依据，以实现人类的依据，以促进人类的范围，并具有促进人类的依据。上皮。 In recent work, we have identified i) four distinguishable epithelial differentiation states (two luminal phenotypes and two basal phenotypes) within human breast tissues that differ on the basis of CD24, EpCAM and CD49f expression, ii) the existence of bipotent progenitors that contribute to structurally distinct elements (ducts and lobule/alveoli), iii) the hormonal combinations that enhance人类上皮细胞中的茎/祖细胞活性，iv）通过TBX3表达的激素生长因子机制可以调节乳腺干样细胞。在该项目的AIM 1中，我们将描绘成人人类乳腺组织的上皮层次结构。在AIM 2中，我们将确定激素生长因子信号如何调节人类乳腺祖细胞活性。我们的研究为人类乳腺祖细胞的身份提供了创新的见解，并提供了关键的分子基础，激素驱动人类乳房祖细胞的形态发生，在病理条件的发展过程中可以作为焦点。