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（申请人提供） 摘要：大多数内部器官都是围绕充满液体的管子建造的，对流体分泌的控制对于它们的发育和功能至关重要。液体分泌的缺陷与一些最普遍的遗传和可获得的病理状况有关，包括囊性纤维化，多囊性肾脏疾病和分泌性腹泻。在细胞水平上，液体分泌由方向性盐离子转运驱动，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。但是，我们仍然需要了解流体分泌如何作为发育力量的作用以及依赖液体分泌的不同过程在整个生物水平上是协调的。为了解决这些基本问题，我已经采用了基于斑马鱼遗传学和生理学的完全整合的方法。我的重点是囊性纤维化跨膜电导调节剂，这是一种氯化物通道，是脊椎动物流体分泌的主要调节剂。拟议的研究计划将导致新见解：（1）流体压力如何塑造发育，以及（2）通过这种力在细胞水平引起的反应； （3）CFTR功能及其活性如何在体内和开发过程中实时调节； （4）我们还将执行一个正向遗传筛选，以识别控制CFTR依赖性和独立流体分泌的突变。这些方法将建立一个新的遗传和生理模型系统，用于研究流体分泌和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剂（CFTR）氯化物通道的活性变化是美国最普遍的两个遗传条件的主要因素，囊性纤维化和多囊肾脏疾病。另外，CFTR通道的不受控制的激活是遗传和感染性分泌性腹泻病理生物生物生物学中的关键元素。后者构成了发展中国家死亡的主要原因。缺乏遗传模型阻碍了CFTR通道的功能调节。此处描述的项目将建立一个研究CFTR功能的遗传和模型系统，并将确定可能构成囊性纤维化和多囊肾脏疾病疗法的新分子靶标的新分子。