Basal body-mediated regulation of ciliary Ca2+ during cilia length control

纤毛长度控制过程中基底体介导的纤毛 Ca2 调节

• 批准号: 9387602
• 负责人: Domenico Fortunato Galati
• 金额: $ 0.06万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9387602
• 关键词: Ablation; Alpha Cell; Area; Binding Proteins; Biology; Body Image; Brain; Buffers; Calcium Channel; Calcium Signaling; Calcium ion; Calmodulin; Cells; Cellular Structures; Chad; Cilia; Colorado; Cystic kidney; Cytoplasm; Defect; Detection; Development; Disease; Ensure; Event; Fellowship; Future; Genetic; Goals; Grant; Human; Human body; Image; Image Analysis; Inborn Genetic Diseases; Ions; Kidney; Length; Lung; Manuscripts; Measures; Mediating; Membrane; Mentors; Microscopy; Microtubules; Movement; Mutation; Organelles; Orthologous Gene; Preparation; Process; Regulation; Research; Research Personnel; Rest; Second Messenger Systems; Sensory; Signal Transduction; Skeletal system; Stimulus; Structure; Testing; Training; Translating; Universities; Writing; appendage; base; body system; career; ciliopathy; developmental disease; digital imaging; experience; experimental study; improved; kinetosome; macromolecule; medical schools; mutant; novel; olfactory sensory neurons; post-doctoral training; public health relevance; ratiometric; skills; success; symposium; therapy design; tool; virtual

 DESCRIPTION (provided by applicant): This proposal outlines a detailed plan for providing the investigator with the scientific training and career developmen skills to ensure a successful postdoctoral training period. His training will be mentored by Drs. Chad Pearson (sponsor) and Lee Niswander (co-sponsor) at the University of Colorado-School of Medicine. The scientific training will focus on how levels of the second messenger ion calcium (Ca2+) are regulated within subcellular signaling structures called cilia, and, in turn, how cilia Ca2+ levels impact ciia structure. Cilia are ubiquitous and evolutionarily conserved appendages that are present on nearly every cell in the human body. Since defects in cilia contribute to a plethora of devastating and currently intractable developmental disorders, this research is expected to improve our basic understanding of cilia biology and inform future ciliopathy therapies. To investigate the relationship between cilia and Ca2+, the investigator has established the hypothesis that cilia Ca2+ levels directly regulate cilia length and that the basal body (BB), which is a small microtubule structure that sits at the base of cilia, regulates the flow of Ca2+ into and out of ciia. To test this this hypothesis, the investigator proposes to accomplish two aims. In Aim1, the investigator will use Ca2+ imaging, optopharmacological manipulation of ciliary Ca2+, and genetic ablation of ciliary Ca2+ levels to directly test how ciliary Ca2+ levels impact cilia lengt. The results from this aim will resolve a fundamental question in cilia biology that is related to how the global manipulation of Ca2+ is able to specifically alter cilia length. In Aim2, the investigator will use similar tools to define how structurally defective BBs alter the flow of Ca2+ into and out of cilia at rest and during signaling events in olfactory sensory neurons. The results from these experiments will illuminate the BB as a novel regulator of ciliary Ca2+ signaling, which will open up a new area of inquiry for the investigator to pursue. In conjunction with a strong mentoring team, the investigator has also established professional developmental goals, such as manuscript preparation, attendance at national conferences and formal coursework in the areas of microscopy, digital image analysis and grant writing to ensure that the scientific training is translated into a future career as an independent investigator.

 描述（由申请人提供）：本提案概述了为研究者提供科学培训和职业发展技能的详细计划，以确保博士后培训期间取得成功。他的培训将由科罗拉多大学医学院的Chad Pearson博士（赞助商）和Lee Niswander博士（共同赞助商）指导。科学培训将集中在第二信使离子钙（Ca2+）的水平是如何在亚细胞信号结构（称为纤毛）中调节的，反过来，纤毛Ca2+水平如何影响ciia结构。纤毛是一种普遍存在且进化上保守的附属物，几乎存在于人体的每一个细胞上。由于纤毛的缺陷会导致过多的破坏性 目前难治性发育障碍，这项研究有望提高我们对纤毛生物学的基本理解，并为未来的纤毛病治疗提供信息。为了研究纤毛和Ca 2+之间的关系，研究者建立了纤毛Ca 2+水平直接调节纤毛长度的假设，以及位于纤毛基部的小微管结构（BB）调节Ca 2+流入和流出纤毛的假设。为了验证这个假设，研究者提出了两个目标。在目标1中，研究者将使用Ca2+成像、睫状体Ca2+的光学药理学操作和睫状体Ca2+水平的遗传消融来直接测试睫状体Ca2+水平如何影响纤毛运动。这一目标的结果将解决纤毛生物学中的一个基本问题，即如何全局操纵Ca2+能够特异性地改变纤毛长度。在目标2中，研究人员将使用类似的工具来定义结构缺陷的BB如何改变Ca2+的流动 在休息时和嗅觉神经元的信号事件中进出纤毛。结果 从这些实验中将阐明BB作为睫状体Ca 2+信号转导的新调节剂，这将为研究人员开辟一个新的研究领域。与强大的辅导团队一起，研究员还制定了专业发展目标，如手稿准备，参加国家会议和显微镜，数字图像分析和赠款写作领域的正式课程，以确保科学培训转化为未来的职业生涯作为一个独立的研究员。