Mechanobiology of Acinar Stability

腺泡稳定性的力学生物学

• 批准号: 8535645
• 负责人: Jan T. Liphardt
• 金额: $ 76.12万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8535645
• 关键词: Abnormal Cell; Accounting; Acinus organ component; Adhesions; Animals; Architecture; Basement membrane; Behavior; Biochemical; Biological Models; Blood Vessels; Breast; CD-ROM; Caliber; Cancer Diagnostics; Cancerous; Cell Survival; Cell model; Cells; Chemicals; Complex; Coupled; Cues; Development; Epithelial Cells; Estrogen Receptors; Extracellular Matrix; Generations; Genetic; Goals; Homeostasis; Hour; Laminin; Lead; Length; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mammary gland; Mechanical Stress; Mechanics; Modeling; Molecular and Cellular Biology; Normal Cell; Property; Role; Signal Transduction; Structure; System; Therapeutic; Time; Tissue Model; Tissues; Tubular formation; Tumor Tissue; behavior influence; cell behavior; cell growth; feeding; malignant breast neoplasm; migration; millimeter; millisecond; nanoscale; neoplastic cell; novel; physical science; pregnant; progesterone receptor negative; pup; research study; response; tool; transmission process; tumor; tumor progression

Mammary epithelial cells (MEC) are organized into tubular structures that terminate in end buds in the virgin animal but end in 'acini' in the mammary glands of pregnant and lactating animals. An acinus is a hollow, roughly spherical ball of cells with a diameter of -50 microns (see center diagram, above). An acinus consists of a single layer of polarized luminal epithelial cells surrounded by a layer of cells referred the as myoepithelium that interacts directly with a laminin-rich basement membrane. Once formed, an acinus is essentially 'stable' in the sense that its average composition, architecture, and size de net change with time until the animal steps feeding the pups. Why is it 'stable' and hew de a small number of specific biochemical and mechanical perturbations lead to less of this stability, and subsequently, malignant transformation? The maintenance of the acinar state involves constant biochemical and mechanical signaling on many length and time scales (nanometers the hundreds of microns; millisecond the hours and days). Some of this signaling involves the transmission of mechanical stresses through the entire acinus, which influences the behaviors of the cells that compose the acinus; these cells in turn can generate forces, which the propagate through the acinus. These forces are transmitted by cell-cell and cell-ECM adhesion. Disrupting the cellular force generation and sensing mechanisms promotes tumor formation [1, 2] (Levental et al. 2009, provided on CD-ROM appendix). A fundamental understanding of these tensional homeostasis mechanisms has broad implications for cancer, since tumor tissues are stiffer than normal and tumor cells show an aberrant response to force and demonstrate altered mechanical properties. These elevated forces and perturbed responsiveness the force enhance tumor cell growth and survival and promote their migration and invasion and even induce new blood vessel formation; all established hallmarks of tumors [1, 3]. The goal of Project 2 is to investigate the role of mechanical forces in acinar homeostasis. This is a tricky task, since forces would be acting on several length and time scales and all must be taken into account.

乳腺上皮细胞（MEC）被组织成管状结构，这些结构在孕妇和哺乳动物的乳腺中以“ acini”结尾，以终止末端的芽终止。腺泡是一个直径为-50微米的空心，大致的细胞球体球（请参见上图，上图）。刺激性由一层层的腔腔上皮细胞组成，该细胞被一层被称为肌上皮，该细胞与富含层粘连蛋白的基底膜直接相互作用。一旦形成，刺激本质上是“稳定”的，因为它的平均成分，结构和大小的净净净变化会随着时间而变化，直到动物步骤喂养幼犬为止。为什么它“稳定”和hew de少数特定的生化和机械扰动会导致这种稳定性较小，随后会导致恶性转化？腺泡状态的维持涉及许多长度和时间尺度上的恒定生化和机械信号传导（纳米数百微米；小时和天数毫秒）。其中一些信号传导涉及机械应力通过整个毒素的传播，这影响了组成刺激的细胞的行为。这些细胞反过来会产生力，从而通过刺激传播。这些力是通过细胞细胞和细胞ECM粘附传播的。破坏细胞力的产生和感应机制会促进肿瘤的形成[1，2]（Levental等，2009，在CD-ROM附录上提供的）。对这些紧张的稳态机制的基本理解对癌症具有广泛的影响，因为肿瘤组织比正常组织更硬，并且肿瘤细胞对力的反应异常，并且表现出改变的机械性能。这些升高的力和扰动的反应能力增强了肿瘤细胞的生长和生存，并促进其迁移和侵袭，甚至诱导新的血管形成。所有已建立的肿瘤标志[1，3]。项目2的目的是研究机械力在腺泡稳态中的作用。这是一项棘手的任务，因为部队将在几个长度和时间尺度上起作用，并且必须考虑所有这些。