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The relationship between Rab11-endosomes and the centrosome during division

Rab11-核内体和中心体在分裂过程中的关系

基本信息

批准号：
10205095
负责人：
Heidi Hehnly
金额：
$ 31.5万
依托单位：
SYRACUSE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-03 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10205095
关键词：
3-Dimensional Acinus organ component Address Animal Model Apical Attention Binding Biosensor Cell Culture Techniques Cell Cycle Cell division Cell membrane Cells Centrioles Centrosome Cilia Congenital Heart Defects Cyst Cytokinesis DNA Sequence Alteration Defect Dependence Development Disease Dissociation Distal Endosomes Event Fluorescence Resonance Energy Transfer Genes Guanosine Triphosphate Phosphohydrolases Hair Interphase Kidney Left Link Liver Measures Membrane Microtubules Mitotic Mitotic spindle Modeling Molecular Monitor Monomeric GTP-Binding Proteins Morphogenesis Mothers Oranges Organ Organelles Pancreas Pathway interactions Patients Play Positioning Attribute Process Proteins Recycling Role Signal Transduction Site Structure Testing Time Tissues Tubular formation Vertebrates Vesicle Zebrafish apical membrane appendage base cell assembly cell type ciliopathy cilium biogenesis cilium motility fluid flow in vivo kidney cell kidney epithelial cell kinetosome live cell imaging optogenetics rab GTP-Binding Proteins tool vesicle transport

项目摘要

SUMMARY STATEMENT: Ciliopathies comprise a group of disorders associated with genetic mutations encoding defective proteins, which result in either abnormal formation or function of cilia. Ciliopathies have been linked to defects in molecular pathways organized at the primary cilium's basal body/centrosome and the primary cilium itself. Patients suffering from ciliopathies can display defects in left/right asymmetry, congenital cardiac defects, and formation of cysts in multiple organs including liver, pancreas and kidney. In vertebrates, motile cilia located in an organ of asymmetry play an important role in left-right development. Evidence from model organisms, such as zebrafish organ of asymmetry (Kupffer's Vesicle, KV), indicates that conserved cilia-driven left-right flow establishes left- right signals to regulate target genes to control left/right asymmetry. This project addresses the question: How do ciliated cells develop into a functional polarized organ? We propose this occurs through a sequential process that starts with cell division, polarity formation, and finishes with cilia assembly. If a ciliated organ wants to expand its central lumen, cells need to re-enter the cell cycle and correctly position its mitotic spindle along the longest axis parallel to the expanding lumen. We found that both Rab11-associated endosomes and a centrosome protein, cenexin, regulate the positioning of the mitotic spindle and ciliogenesis (Hehnly and Doxsey, 2014; Hung et al., 2016), but whether they act together during these processes has not been examined. During interphase, Rab11-endosomes associate with mother centriole sub-distal appendages where cenexin resides (Hehnly et al., 2012). Rab11 and a second GTPase, Rab8, can directly interact with cenexin. In addition, a GTPase cascade has been identified between Rab11 and Rab8 during ciliogenesis and apical membrane initiation, but if it requires the centrosome or occurs during specific points of the cell cycle is unknown. We will test the overall hypothesis that anchoring Rab11 and/or Rab8 by the mother centriole appendage protein, cenexin, is required for spindle positioning, polarity formation and/or ciliogenesis. To test this we will determine whether the centrosome can modulate Rab11 and/or Rab8 activity (Aim 1) and determine when during the cell cycle Rab11 and Rab8 activity is required to regulate tissue morphogenesis (Aim 2). This will be accomplished by using a 3-D kidney epithelial cell culture model and an in vivo developmental model, zebrafish KV formation, to identify a framework for how polarity formation relates to the cell cycle.!

综述：纤毛病包括一组与遗传相关的疾病