Tensile stress in orienting planar cell polarity

定向平面细胞极性的拉应力

• 批准号: 8147045
• 负责人: Christopher Robert Kintner
• 金额: $ 26.9万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8147045
• 关键词: Affect; Anterior; Apical; Biocompatible Materials; Biological Assay; Biological Models; Brain; Cell Differentiation process; Cell Polarity; Cells; Cerebral Ventricles; Cilia; Cues; Defect; Development; Developmental Process; Devices; Diagnosis; Distal; Ectoderm; Embryo; Embryonic Development; Epithelium; Event; Fibronectins; Glass; Goals; Health; Homologous Gene; Human; Individual; Lung; Maps; Measures; Mediating; Mesoderm; Modeling; Morphology; Mucous body substance; Nature; Organ; Pathway interactions; Pattern; Play; Primary Ciliary Dyskinesias; Process; Research; Role; Signal Pathway; Signal Transduction; Skin; Specific qualifier value; Staging; Stress; Study models; Sum; Surface; Syndrome; Testing; Time; Tissues; To specify; Work; base; body system; fluid flow; gastrulation; human disease; novel; prospective; reproductive; research study; respiratory

DESCRIPTION (provided by applicant): In many organ systems, cells projecting hundreds of beating cilia, called multiciliate cells, produce a vigorous fluid flow that transports biological materials along luminal surfaces. Multiciliate cells populate the respiratory and reproductive tracts, and the ventricles of the brain, and the flow they produce has significant implications for human health. To be effective in organ function, ciliary flow has to direct along a specific axis: in the lung, for example, flow propels mucus out of rather than deeper into the airways. To produce directed flow, developing epithelia need to acquire a planar axis, thus orienting cilia beating within a cell, as well as between cells. To determine how multiciliate cells acquire planar cell polarity (PCP), we have pioneered a model system, namely the X. laevis larval skin. Multiciliate cells begin to differentiate in the developing skin soon after gastrulation, producing a vigorous ciliary flow that invariably is directed from anterior to posterior. A global patterning event that occurs during gastrulation is known to fix the direction of ciliary flow, but nothing is known about the mechanisms that mediate this patterning event as is the case in all other known examples of PCP. In this exploratory proposal, we will test a new model where the direction of planar polarity is dictated in part by the orientation of tensile stress that occurs in the tissue during embryogenesis. In the case of the skin, this tensile stress occurs during gastrulation via the forces generated by mesoderm during involution and axial elongation. Specifically, we will employ a device, called the tractor pull, to apply oriented stress to isolated developing skin, at stages when the planar axis is normally established. These experiments will extend on preliminary findings, determine the parameters by which oriented stress can specify a planar axis, and determine whether oriented stress works upstream or in parallel with the PCP signaling pathway. In sum, the experiments proposed here will provide an important proof of principle, thus establishing a new model for studying how forces in the embryo sculpt and pattern tissues. PUBLIC HEALTH RELEVANCE: Multiciliate cells play important roles in human health by generating directed fluid flow in the brain, lung and reproductive tract, but the mechanisms that orient flow direction in relation to an organ axis are poorly understood. To study these mechanisms, the proposed research will employ a model system to test a novel hypothesis where tensile stress incurred by a developing tissue acts to orient the direction of ciliary flow. Results from the proposed experiments will potentially establish a new paradigm for how the direction of ciliary flow is established during development, and will have implications for diagnosis and treatment of human disease that affect ciliated epithelia, such as the ciliary defects that occurs during primary ciliary dyskinesia and Kartegener's syndrome.

描述（由申请人提供）：在许多器官系统中，投射数百个跳动纤毛的细胞（称为多纤毛细胞）产生强劲的流体流，沿着管腔表面运输生物材料。多纤毛细胞分布在呼吸道、生殖道以及脑室中，它们产生的流量对人类健康具有重大影响。为了有效地发挥器官功能，纤毛流必须沿着特定的轴引导：例如，在肺部，纤毛流将粘液推出气道，而不是深入气道。为了产生定向流动，发育中的上皮细胞需要获得平面轴，从而定向细胞内以及细胞之间的纤毛跳动。为了确定多纤毛细胞如何获得平面细胞极性（PCP），我们开创了一个模型系统，即非洲虎幼虫皮肤。原肠胚形成后不久，多纤毛细胞开始在发育中的皮肤中分化，产生始终从前部向后部引导的旺盛的纤毛流。已知原肠胚形成期间发生的全局图案化事件可固定纤毛流动的方向，但对于介导该图案化事件的机制一无所知，就像所有其他已知的 PCP 示例中的情况一样。在这个探索性提案中，我们将测试一个新模型，其中平面极性的方向部分由胚胎发生过程中组织中发生的拉应力的方向决定。就皮肤而言，这种拉伸应力在原肠胚形成过程中通过中胚层在复旧和轴向伸长过程中产生的力而发生。具体来说，我们将使用一种称为牵引器拉力的装置，在平面轴正常建立的阶段向孤立的发育中的皮肤施加定向应力。这些实验将扩展初步发现，确定定向应力可以指定平面轴的参数，并确定定向应力是在 PCP 信号通路的上游还是与 PCP 信号通路平行起作用。总之，这里提出的实验将提供重要的原理证明，从而建立一个新的模型来研究胚胎中的力如何塑造和图案组织。 公共健康相关性：多纤毛细胞通过在大脑、肺和生殖道中产生定向流体流动，在人类健康中发挥着重要作用，但相对于器官轴定向流动方向的机制却知之甚少。为了研究这些机制，拟议的研究将采用一个模型系统来测试一个新的假设，即发育中的组织产生的拉伸应力可以定向纤毛流动的方向。所提出的实验结果将有可能为发育过程中如何建立纤毛流动方向建立一个新的范例，并将对影响纤毛上皮的人类疾病的诊断和治疗产生影响，例如原发性纤毛运动障碍和卡特格纳综合征期间发生的纤毛缺陷。