The Role of Primary Cilia in Mammary Gland Biology

初级纤毛在乳腺生物学中的作用

基本信息

批准号：
7294540
负责人：
KIMBERLY M MCDERMOTT
金额：
$ 8.33万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-15 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7294540
关键词：
Alveolar Architecture Bardet-Biedl Syndrome Biological Biology Bos taurus Cattle Cell surface Cells Cilia Communication Data Development Duct (organ) structure Ductal Electron Microscopy Environment Epithelial Epithelial Cells Epithelial-Stromal Communication Erinaceidae Etiology Event Family member Fatty acid glycerol esters Fibroblasts Functional disorder Gene Targeting Hereditary Disease Human Invaded Lactation Liquid substance Lobular Mammary Gland Parenchyma Mammary gland Mediating Membrane Modeling Morphogenesis Mus Mutation Myoepithelial Myoepithelial cell Numbers Organelles Oryctolagus cuniculus Pancreas Pattern Phenotype Play Polycystic Kidney Diseases Positioning Attribute Pregnancy Primary Ciliary Dyskinesias Process Puberty Purpose Receptor Mediated Signal Transduction Reporter Research Personnel Retina Role Sensory Signal Transduction Stream Surface Tissues Transplantation Trees cell motility cell type design functional loss immunocytochemistry in vivo insight interstitial malignant breast neoplasm programs receptor sperm cell

项目摘要

DESCRIPTION (provided by applicant): The primary cilium is a membrane-enclosed organelle that projects from the surface of the cell and acts as the cell's antennae to communicate with its environment. The primary cilium senses signals from the environment and transduces receptor-mediated signaling events that control fundamental processes such as proliferation, differentiation and polarity. Furthermore, loss of ciliary function results in a number of developmental abnormalities and genetic diseases. I have demonstrated that the majority of primary cilia found in the murine and human mammary glands are expressed on the surface of myoepithelial cells. Nothing is known about the function of the cilium in this environment. Cilia projecting from the surface of myoepithelial cells are ideally positioned to play a sensory role to regulate stromal-epithelial as well as myoepitnelial-luminal epithelial interactions. Communication between the micrioenvironment plays a critical role in the expansion and function of the mammary ductal tree during development, pregnancy, lactation and involution. I hypothesize that cilia mediate stromal-epithelial and myoepithelial-luminal epithelial communications to regulate mammary gland development, pregnancy, and lactation. The specific aims described in this application are designed to characterize the pattern of expression of primary cilia and determine the function of primary cilia in normal mammary gland development, pregnancy, lactation and involution. I will analyze the mammary glands from murine models of ciliary dysfunction to determine whether ductal invasion, branching morphogenesis, tissue architecture, lobular- alveolar differentiation, lactation and involution are abrogated by loss of functional cilia. Preliminary data indicate that ductal invasion, branching morphogenesis, lobular-alveolar differentiation and lactation are decreased in the absence of functional cilia. Preliminary data also suggests that canonical Wnt signaling is increased and noncanonical Wnt signaling is decreased in the absence of functional cilia. These exciting results suggest that the primary cilium is involved in regulating Wnt signaling during mammary gland development. Given that cilia appear to control processes important in mammary gland development and breast cancer, such as ductal invasion, branching morphogenesis and differentiation, developing a better understanding of the mechanisms by which cilia function may provide important insight into the etiology and progression of breast cancer. I also believe studying primary cilia in the mammary gland will uncover ciliary functions that will contribute to a better understanding of the many genetic diseases caused by ciliary dysfunction.

描述（由申请人提供）：主要的纤毛是一种膜封闭的细胞器，它是从细胞表面投射出来的，并充当与环境通信的细胞触角。原发性纤毛从环境中感应信号，并传达受体介导的信号传导事件，以控制基本过程，例如增殖，分化和极性。此外，睫状功能的丧失导致许多发育异常和遗传疾病。我已经证明，在鼠和人类乳腺中发现的大多数原发性纤毛都在肌上皮细胞的表面表达。在这种环境中纤毛的功能一无所知。从肌上皮细胞表面投射的纤毛可以在调节基质上皮以及肌长鼻luminal上皮相互作用方面发挥感官作用。微环境之间的交流在发育，妊娠，泌乳和互动过程中在乳腺导管树的扩张和功能中起关键作用。我假设纤毛介导基质上皮和肌上皮上皮上皮通信，以调节乳腺发育，妊娠和泌乳。本应用中描述的具体目的旨在表征原发性纤毛的表达方式，并确定原发性纤毛在正常乳腺发育，妊娠，泌乳和互动中的功能。我将分析来自睫状功能障碍的鼠模型的乳腺，以确定导管侵袭，分支形态发生，组织结构，小叶间分化，泌乳和参与是否因功能纤毛的丧失而消除。初步数据表明，在没有功能性纤毛的情况下，导管浸润，分支形态发生，小叶 - 肺泡分化和泌乳降低。初步数据还表明，在没有功能性纤毛的情况下，规范的Wnt信号传导增加，非规范WNT信号传导降低。这些令人兴奋的结果表明，主要的纤毛参与调节乳腺发育过程中的Wnt信号传导。鉴于纤毛似乎控制了对乳腺发育和乳腺癌重要的重要过程，例如导管侵袭，分支形态发生和分化，因此可以更好地理解纤毛功能可以为乳腺癌的病因和进展提供重要洞察力的机制。我还认为，研究乳腺中的原发性纤毛会发现睫状功能，这将有助于更好地理解纤毛功能障碍引起的许多遗传疾病。