Calcium regulation of flagellar motility

钙对鞭毛运动的调节

• 批准号: 7657408
• 负责人: Elizabeth F Smith
• 金额: $ 31.74万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7657408
• 关键词: Address; Affect; Affinity; Architecture; Binding; Biochemical; Blood Circulation; Buffers; Calcium; Calcium Channel; Calmodulin; Calmodulin-Binding Proteins; Cerebrospinal Fluid; Chlamydomonas; Cilia; Complement component C1s; Complex; Cues; Data; Defect; Development; Dynein ATPase; Electron Microscopy; Excision; Exhibits; Family; Fertility; Flagella; Foundations; Funding; Gene Expression; Generations; Goals; Hydrocephalus; Knock-out; Left; Link; Mammals; Mediating; Methods; Microtubules; Modeling; Molecular; Motor; Organelles; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Process; Proteins; Radial; Randomized; Regulation; Respiratory System; Respiratory distress; Respiratory tract structure; Role; Second Messenger Systems; Shapes; Signal Transduction; Signal Transduction Pathway; Slide; Speed; Structure; System; Testing; Upper arm; Work; base; cell motility; cell type; design; extracellular; interest; knock-down; meetings; mutant; protein protein interaction; public health relevance; research study; response; scaffold; second messenger; sensor; sperm cell

DESCRIPTION (provided by applicant): The goal of this project is to understand the mechanism by which calcium alters the size and shape of ciliary and flagellar bends to control motility. In mammals, motile cilia / flagella are required for sperm propulsion, removal of debris from the respiratory tract, circulation of cerebrospinal fluid, and even for determination of the left-right body plan during development. As a consequence, defects in motility may result in impaired fertility, respiratory distress, hydrocephalus, and/or randomization of the left-right body axis. The architecture and molecules which comprise these organelles are remarkably conserved. Therefore, fundamental principles for motility obtained from studies of any single cell type are generally applicable to all eukaryotic cilia and flagella. Understanding how dynein is regulated to produce the complex waveforms typical of beating cilia / flagella is still the most pressing unanswered question in the field of ciliary motility. Substantial data has contributed to a model in which the axonemal microtubules act as a scaffold for the assembly of molecules that form a signal transduction pathway that ultimately regulates dynein. The second messenger calcium impacts upon these signal transduction pathways to alter beating in response to extracellular cues. The discovery that calmodulin (CaM) is a key calcium sensor and that highly conserved CaM-binding proteins are localized to axonemal structures known to play a role in motility form the foundation for this work. The proposed experiments are designed to test the hypothesis that specific CaM-binding proteins are part of a signal transduction network that alters motility in response to calcium. The Specific Aims of this proposal are to 1) develop strains with defects in CaM interactors; 2) test the hypothesis that central apparatus associated CaM plays a role in modulating dynein activity on specific doublet microtubules; and 3) test the hypothesis that a spoke-associated CaM binding complex, the CSC, is both a structural and functional component of a signal transduction pathway that modulates dynein activity. These studies have the potential to define a molecular mechanism for CaM mediated signal transduction that includes specific protein-protein interactions acting as switches to control dynein activity, as well as the broader potential to define new principles for the targeting and anchoring of molecules that define signal transduction pathways that regulate the dynein family of motors. PUBLIC HEALTH RELEVANCE: We are interested in defining mechanisms for calcium regulation of ciliary and flagellar motility. In mammals, motile cilia / flagella are required for sperm propulsion, removal of debris from the respiratory tract, circulation of cerebrospinal fluid, and even for determination of the left-right body plan during development (reviewed in Satir and Christensen, 2006). As a consequence, defects in motility may result in impaired fertility, respiratory distress, hydrocephalus, and/or randomization of the left-right body axis (reviewed in Badano et al, 2006).

描述（由申请人提供）：该项目的目的是了解钙改变睫状和鞭毛弯曲以控制运动的机制。在哺乳动物中，精子推进，从呼吸道中去除碎屑，脑脊液的循环，甚至确定发育过程中左右身体计划所必需的纤毛 /鞭毛。结果，运动性缺陷可能导致左右身体轴的生育能力受损，呼吸窘迫，脑积水和/或随机分组。组成这些细胞器的结构和分子非常保守。因此，从任何单个细胞类型的研究获得的运动性基本原理通常适用于所有真核纤毛和鞭毛。了解如何调节动力蛋白以产生击败纤毛 /鞭毛的典型的复杂波形仍然是纤毛运动领域中最紧迫的未解决问题。实质性数据有助于一个模型，在该模型中，轴突微管充当分子组装的支架，该分子形成了最终调节动力蛋白的信号转导途径。第二信使钙会影响这些信号转导途径，以响应细胞外提示改变跳动。发现钙调蛋白（CAM）是一个关键的钙传感器，并且高度保守的CAM结合蛋白被定位于已知在运动中发挥作用的轴突结构，这是这项工作的基础。所提出的实验旨在测试以下假设：特定的CAM结合蛋白是信号转导网络的一部分，该网络会改变对钙的运动性。该提案的具体目的是1）发展CAM相互作用者缺陷的菌株； 2）检验以下假设：中央设备相关的凸轮在调节特定双重微管上的动力蛋白活性中起作用； 3）检验以下假设：辐条相关的CAM结合复合物CSC既是调节Dynein活性的信号转导途径的结构和功能成分。这些研究具有定义CAM介导的信号转导的分子机制，其中包括特定的蛋白质 - 蛋白质相互作用，用作控制动力蛋白活性的转换，以及定义分子定义和锚定定义信号转导途径的分子定义新原理的更广泛的潜力，从而调节了调节运动型动力蛋白家族的信号转导途径。 公共卫生相关性：我们有兴趣定义纤毛和鞭毛运动的钙调节机制。在哺乳动物中，精子推进，从呼吸道中去除碎屑，脑脊液的循环，甚至确定发育过程中左右身体计划所必需的纤毛 /鞭毛（在Satir和Christensen，2006年进行了审查）。结果，运动性缺陷可能导致左右身体轴的生育能力受损，呼吸窘迫，脑积水和/或随机分组（Badano等人，2006年）。