RE: Regulation of mammary branching morphogenesis by Slit/Robo 1 signaling

RE: Slit/Robo 1 信号调节乳腺分支形态发生

• 批准号: 8623914
• 负责人: LINDSAY E HINCK
• 金额: $ 0.54万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-29 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8623914
• 关键词: 3-Dimensional; Adhesives; Basal Cell; Biochemical; Biological; Biological Models; Biology; Breast; Cancer Biology; Cancer Etiology; Cell Adhesion; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Cessation of life; Complex; Cues; DNA Sequence Rearrangement; Data; Development; Developmental Cell Biology; Environment; Epithelial; Extracellular Matrix Proteins; Family; Gland; Goals; Growth; Image; Knock-out; Knowledge; Malignant - descriptor; Malignant Neoplasms; Mammary gland; Mediating; Membrane; Modeling; Morphogenesis; Mus; Mutation; Myoepithelial cell; Neoplasm Metastasis; Noninfiltrating Intraductal Carcinoma; Organ; Organogenesis; Organoids; Outcomes Research; Pathway interactions; Phenotype; Play; Population; Primary Cell Cultures; Principal Investigator; Process; Prostate; Regulation; Reporting; Research; Role; Salivary; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Stem cells; Stratum Basale; Structure; System; Techniques; Testing; Tissues; Transcriptional Activation; Transforming Growth Factors; Transgenic Mice; Transplantation; Up-Regulation; WNT Signaling Pathway; Woman; cancer stem cell; cell growth; extracellular; gain of function; in vivo; infiltrating duct carcinoma; inhibitor/antagonist; loss of function mutation; malignant breast neoplasm; mammary epithelium; mammary gland development; mouse model; novel; progenitor; programs; protein function; receptor; research study; self-renewal; stem; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): A core objective of tissue biology is to understand how cells interact to generate tissues and organs. While great strides have been made in defining signaling pathways that mediate cellular interactions, there is a fundamental gap in our knowledge concerning how these signaling systems are integrated during mammalian organogenesis. Bridging this knowledge gap is important in identifying druggable targets for cancer, as tumor growth and progression is marked by disorganization of tissue structure, and deregulation of specialized cell populations, such as stem cells. The goal of this application is to understand how extracellular factors, SLITs, influence tissue morphogenesis by regulating the proliferation of a single layer of basal cells in which stem cells reside. Here, mammary branching morphogenesis is used as a model system and, guided by strong preliminary data, the following model is investigated in which a key inhibitor of mammary branching, TGF-21, restrains basal cell proliferation and adhesion by upregulating signaling through the SLIT/ROBO1 pathway. This, in turn, controls basal cell growth and branching morphogenesis by increasing the adhesive functions of 2-catenin at the membrane, at the expense of its proliferative functions in the nucleus. A variety of cell biological, imaging and biochemical techniques will be employed, as well as powerful transplant techniques to manipulate genetically modified mammary tissue. Three hypotheses are tested in three Aims: I) that TGF-21 upregulates Robo1 expression, specifically in basal cells, and that this inhibits branching by restraining basal cell growth; II) that SLIT/ROBO1 signaling opposes the actions of canonical WNTs by altering the subcellular localization of 2-catenin and promoting its cell adhesive functions at the expense of its transcriptional functions; and III), that SLITs are non-renewal factors for stem cells that function to counter the self-renewal signals of canonical WNT signaling by regulating 2-catenin. Together, these experiments will have a positive impact on cancer biology of breast and other glandular organs containing basal stem cell subpopulations (e.g. prostate, salivary etc), because they delineate a novel tumor suppressive signaling network that appears to function in stem cells.

描述（由申请人提供）：组织生物学的核心目标是了解细胞如何相互作用以生成组织和器官。尽管在定义介导细胞相互作用的信号通路方面取得了长足的进步，但在我们的知识中，关于这些信号系统如何在哺乳动物器官发生过程中积分的基本差距。桥接该知识差距对于鉴定癌症的可药靶标很重要，因为肿瘤的生长和进展是组织结构混乱的标志，并且对特殊细胞群体（例如干细胞）的放松管制。该应用的目的是了解细胞外因子，缝隙，如何通过调节干细胞驻留的单层基底细胞的增殖来影响组织形态发生。在这里，乳腺分支形态发生用作模型系统，在强有力的初步数据的引导下，研究了以下模型，其中乳腺分支的关键抑制剂TGF-21（TGF-21）通过SLIT/ROBO1途径来限制基础细胞的增殖和粘附。反过来，这通过增加膜上2-catenin的粘附功能来控制基础细胞的生长和分支形态发生，而其牺牲了其在细胞核中的增殖功能。将采用多种细胞生物学，成像和生化技术，以及强大的移植技术来操纵转基因乳腺组织。三个假设在三个目的中进行了检验：i）TGF-21上调Robo1的表达，特别是在基础细胞中，并且通过限制基础细胞生长来抑制分支； ii）缝制/robo1信号传递通过改变2-catenin的亚细胞定位并促进其细胞粘附功能，以其转录功能为代价，可以反对规范WNT的作用； iii），对于通过调节2-catenin来应对规范Wnt信号传导的自我更新信号的干细胞的非更新因素。总之，这些实验将对乳腺癌和其他含有基础干细胞亚群的癌症生物学（例如前列腺，唾液等）产生积极影响，因为它们描绘了似乎在干细胞中起作用的新型肿瘤抑制信号网络。