Developmental Physiology of Ciliated Epithelia

纤毛上皮的发育生理学

• 批准号: 7736199
• 负责人: Christopher Robert Kintner
• 金额: $ 41.67万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-21 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7736199
• 关键词: Abbreviations; Acids; Address; Affect; Amphibia; Anterior; Apical; Asthma; Bicarbonates; Biocompatible Materials; Biological Models; Carbonates; Cell Differentiation process; Cell Polarity; Cells; Cellular Structures; Cerebral Ventricles; Chronic; Chronic Obstructive Airway Disease; Cilia; Cues; Cystic Fibrosis; Data; Defect; Development; Diagnosis; Disease; Duct (organ) structure; Ectopic Pregnancy; Embryonic Development; Epithelial Cells; Epithelium; Female; Fertilization; Gene Targeting; Genes; Health; Homologous Gene; Human; Image; Intercalated Cell; Kidney; Lead; Lung; Mammalian Oviducts; Mediating; Modeling; Molecular; Morbidity - disease rate; Mucociliary Clearance; Mucous body substance; Mucus-Secreting Cell; Organ; Pattern; Physiology; Play; Positioning Attribute; Process; Property; Protons; Radial; Regulation; Research; Respiratory Failure; Respiratory System; Respiratory tract structure; Role; Signal Pathway; Signal Transduction; Skin; Specialized Epithelial Cell; Surface; Testing; Time; Tissues; Vertebrates; Work; Xenopus; Xenopus laevis; base; body system; cell type; fluid flow; genetic analysis; human disease; intercalation; kinetosome; loss of function; polarized cell; progenitor; public health relevance; reproductive; research study; transcription factor; two-dimensional

DESCRIPTION (provided by applicant): In many organ systems, epithelia produce a vigorous ciliary flow that transports biological materials along luminal surfaces and a loss of this flow has significant implications for human health. The respiratory tract, for instance, is a ciliated epithelium where flow is used to transport a protective mucus layer and a mechanism for clearing the lung after tissue damage. As a consequence, loss of ciliary flow in the respiratory tract is a contributing factor to morbidity in chronic asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Despite their importance to human health, the cellular and molecular mechanisms that underlie the development and function of ciliated epithelia are still largely unknown. We propose to study these mechanisms using a tractable model system, the Xenopus larval skin. The larval skin is one of the earliest organs to form during embryonic development, can be easily imaged, and is extremely tractable to a genetic analysis. In addition, the larval skin contains specialized epithelia cell types that are the hallmark of ciliated epithelia, including the multi-ciliate cells specialized to produce ciliary flow, cells specialized to produce mucus, and cells specialized for acid/base transport. Using this model, the proposed experiments will address two Aims. In the first Aim, experiments are proposed to determine the mechanisms that orient ciliated cells so that beat in the same direction. This property of ciliated cells, called planar cell polarity, underlies the ability to produce long range flow that is directed along the appropriate tissue axis. These experiments will dissect the patterning cues that orient ciliated cells when they form, and the role of flow in refining ciliated cell orientation. In the second Aim, experiments are proposed to determine the mechanisms that underlie the formation of cells involved in acid/base transport. These cells are directly analogous to the intercalated cells in the kidney, which play critical roles in pH regulation. These experiments will determine the role of transcription factors in the formation of these cells, and how these cells become specialized to secrete protons or the base equivalent, carbonate. The results from the experiments outlined in these Aims will provide basic information about the formation and function of specialized cells types found in ciliated epithelia, with implications for the diagnosis and treatment of human diseases that cause defects in mucociliary transport and pH mis-regulation. PUBLIC HEALTH RELEVANCE: Specialized epithelia play important roles in human health by generating ciliary flow in such organs as the lung and the female reproductive tract but how the specialized cell types that make up these epithelia form during embryogenesis remains largely unknown. The proposed research will use the Xenopus larval skin as a model system to determine the developmental mechanisms that underlie the formation of two specialized epithelial cell types, namely cells that are multi-ciliated and produce fluid flow and cells that mediate acid/base transport. A better understanding of these cell types will aid in the diagnosis and treatment of human disease that affect ciliated epithelia, such as the mucus clearance defects that occurs during chronic asthma, cystic fibrosis, and chronic obstructive pulmonary disease.

描述（由申请人提供）：在许多器官系统中，上皮产生剧烈的睫状流，该纤毛流沿着腔表面运输生物材料，并且这种流量的损失对人类健康具有重要意义。例如，呼吸道是一种纤毛上皮，在该上皮上，流动用于运输保护性粘液层和组织损伤后清除肺部的机制。结果，呼吸道中睫状流的损失是导致慢性哮喘，囊性纤维化和慢性阻塞性肺部疾病的发病率的一个因素。尽管它们对人类健康的重要性，但基于纤毛上皮的发展和功能的细胞和分子机制仍然很大程度上是未知的。我们建议使用可拖动的模型系统（爪蟾幼虫皮肤）研究这些机制。幼虫皮是在胚胎发育过程中最早形成的器官之一，很容易成像，并且对遗传分析非常易。此外，幼体皮肤含有专门的上皮细胞类型，这些细胞类型是纤毛上皮的标志，包括专门产生纤毛流的多丝状细胞，专门产生粘液的细胞以及专门用于酸/碱基运输的细胞。使用此模型，提出的实验将解决两个目标。在第一个目标中，提出了实验来确定定向纤毛细胞的机制，以便沿相同的方向跳动。这种称为平面细胞极性的纤毛细胞的特性是产生沿适当组织轴的远程流动的能力。这些实验将剖析形成时纤毛细胞的模式提示，以及流动在精炼纤毛细胞方向中的作用。在第二个目标中，提出了实验来确定基于酸/碱转运的细胞形成的机制。这些细胞直接类似于肾脏中插入的细胞，在肾脏中起着关键作用。这些实验将确定转录因子在这些细胞形成中的作用，以及这些细胞如何专门用于分泌质子或基础等效碳酸盐。这些目标中概述的实验的结果将提供有关纤毛上皮细胞中特殊细胞类型的形成和功能的基本信息，这对诊断和治疗人类疾病的诊断和治疗产生了导致粘膜切换和pH错误调节的缺陷。公共卫生相关性：专业上皮通过在肺和女性生殖道等器官中产生睫状流，而在人类健康中起重要作用，但是在胚胎发生过程中构成这些上皮形成的专门细胞类型如何仍然很大程度上不明。拟议的研究将使用爪蟾幼虫皮作为模型系统，以确定形成两种专用上皮细胞类型的发育机制，即多丝化的细胞，并产生介导酸/碱基运输的流体流量和细胞。对这些细胞类型的更好理解将有助于影响影响纤毛上皮的人类疾病，例如在慢性哮喘，囊性纤维化和慢性阻塞性肺部疾病期间发生的粘液清除缺陷。