Discovering New Regulators of CFTR and Fluid Secretion in Zebrafish

发现斑马鱼 CFTR 和液体分泌的新调节因子

• 批准号: 7849327
• 负责人: Michel Bagnat
• 金额: $ 234万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849327
• 关键词: Address; Biological Models; Cause of Death; Chloride Channels; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Defect; Development; Diarrhea; Fluids and Secretions; Genetic; Genetic Models; Genetic Screening; Hereditary Disease; Indium; Inherited; Ion Transport; Ions; Lead; Link; Liquid substance; Molecular Target; Mutation; Organ; Physiology; Polycystic Kidney Diseases; Process; Regulation; Research; Shapes; Sodium Chloride; Time; Tube; Vertebrates; Water; Whole Organism; Zebrafish; abstracting; base; in vivo; insight; physiologic model; pressure; public health relevance; response

DESCRIPTION (Provided by the applicant) Abstract: Most internal organs are built around fluid-filled tubes and control of fluid secretion is essential for their development and function. Defects in fluid secretion have been linked to some of the most prevalent genetic and acquired pathological conditions, including Cystic Fibrosis, Polycystic Kidney Disease and secretory diarrheas. At the cellular level, fluid secretion is driven by directional salt ion transport which is then followed by water. Several key channels and pores responsible for ion and water transport have been identified. However, we still need to understand how fluid secretion functions as a developmental force and how different processes that depend on fluid secretion are coordinated at the whole organism level. To address these fundamental problems I have embarked on a fully integrated approach based on zebrafish genetics and physiology. My focus is on the Cystic Fibrosis Transmembrane conductance Regulator, a chloride channel that is the major regulator of fluid secretion in vertebrates. The proposed research plan will lead to new insights into: (1)how fluid pressure shapes development and (2)the responses elicited at the cellular level by this force; (3)CFTR function and how its activity is regulated in vivo and in real time during development; (4)We will also carry out a forward genetic screen to identify mutations controlling CFTR-dependent and independent fluid secretion. These approaches will establish a new genetic and physiologic model system for studying the functional regulation and developmental potential of fluid secretion and CFTR activity. Public Health Relevance: Changes in the activity of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride channel is a major factor in the two genetic conditions most prevalent in the US, Cystic Fibrosis and Polycystic Kidney Disease. In addition, uncontrolled activation of the CFTR channel is a key element in the pathopysiology of inherited and infectious secretory diarrheas. The latter constitutes the leading cause of death in the developing world. Understanding the functional regulation of the CFTR channel has been hindered by the lack of a genetic model. The project described here will establish a genetic and model system to study CFTR function and will identify new molecules that may constitute new molecular targets for Cystic Fibrosis and Polycystic Kidney Disease therapy.

描述（由申请人提供） 翻译后摘要：大多数内部器官是建立在充满液体的管和液体分泌的控制是必不可少的，他们的发展和功能。液体分泌缺陷与一些最普遍的遗传和获得性病理状况有关，包括囊性纤维化、多囊肾病和分泌性肾小球疾病。在细胞水平，液体分泌是由定向盐离子运输驱动的，然后是水。已经确定了负责离子和水运输的几个关键通道和孔。然而，我们仍然需要了解液体分泌是如何作为一种发育力量发挥作用的，以及依赖于液体分泌的不同过程是如何在整个生物体水平上协调的。为了解决这些基本问题，我已经开始了一个基于斑马鱼遗传学和生理学的完全集成的方法。我的重点是囊性纤维化跨膜电导调节器，氯离子通道，是脊椎动物液体分泌的主要调节器。拟议的研究计划将导致新的见解：（1）流体压力如何塑造发育和（2）这种力量在细胞水平上引起的反应;（3）CFTR功能及其活性如何在体内和发育过程中的真实的时间进行调节;（4）我们还将进行正向遗传筛选，以确定控制CFTR依赖性和独立性液体分泌的突变。这些方法将建立一个新的遗传和生理模型系统，研究液体分泌和CFTR活性的功能调节和发育潜力。 公共卫生相关性：囊性纤维化跨膜电导调节器（CFTR）氯离子通道活性的变化是美国最常见的两种遗传性疾病囊性纤维化和多囊肾病的主要因素。此外，CFTR通道的不受控制的激活是遗传性和感染性分泌型乳腺炎病理生理学中的关键因素。后者是发展中国家的主要死亡原因。理解CFTR通道的功能调节由于缺乏遗传模型而受到阻碍。这里描述的项目将建立一个遗传和模型系统来研究CFTR功能，并将识别可能构成囊性纤维化和多囊肾病治疗新分子靶点的新分子。