Identification of signals that extrude an apoptotic cell from an epithelium

鉴定从上皮中挤出凋亡细胞的信号

基本信息

批准号：
7430578
负责人：
Jody Snow Rosenblatt
金额：
$ 225.5万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7430578
关键词：
Acetone Acid Phosphatase Actins Actomyosin Address Adherens Junction Adult Affinity Affinity Chromatography Alcohol consumption Alkaline Phosphatase Animal Model Animals Annexins Anoikis Antibiotic A23187 Antibodies Apoptosis Apoptotic Area Asthma Autophagocytosis Award Bacterial Infections Bax protein Binding Binding Proteins Biochemical Biochemistry Biological Biological Assay Biological Markers Biological Models Biology Blood Blood Circulation Boston Brefeldin A Caenorhabditis elegans Calcium Cancer Biology Canis familiaris Carbon Carcinoma Caspase Caspase Inhibitor Cell Count Cell Death Cell Death Induction Cell Differentiation process Cell Line Cell Nucleus Cell membrane Cell surface Cells Cellular biology Centrosome Ceramides Cessation of life Chemicals Chloroform Chromosomes Clinical Cloning Closure Collaborations Commit Complex Condition Conjunctivitis Contracts Crowding Cultured Cells Cytochromes Cytokinesis DNA Data Defect Depth Development Developmental Biology Developmental Process Diagnosis Diagnostic Neoplasm Staging Disease Disruption Drosophila genus Eczema Embryo Endopeptidases England Ensure Environment Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Epidermis Epithelial Epithelial Cells Epithelial cyst Epithelium Equipment Ethers Ethyl Ether Event Exocytosis Faculty Feeling Figs - dietary Film Fishes Focal Adhesion Kinase 1 Fractionation Funding G-Protein-Coupled Receptors Gene Family Genes Genetic Genetic Screening Genomic Instability Glycolipids Goals Grant Graph Green Fluorescent Proteins Growth Factor Hand Harvest Heart High Pressure Liquid Chromatography Homeostasis Homologous Gene Human Hydrolysis Image In Situ Inflammation Injection of therapeutic agent Institutes Integrins Ionophores Kidney Kinetics Knowledge Label Laboratories Lasers Lead Learning Left Length Libraries Life Link Lipase Lipid Biochemistry Lipids Liver Localized London Long-Term Effects Maintenance Malignant Neoplasms Mammalian Cell Mass Spectrum Analysis Measures Mediating Medical Membrane Lipids Mesenchyme Methanol Methods Micelles Microtubules Mitochondria Mitosis Mitotic spindle Modeling Modification Type Molecular Biology Molecular Weight Mono-S Morphogenesis Movement Mus Mutation Myosin ATPase Myosin Type II Nature Necrosis Neoplasm Metastasis Neural Crest Normal tissue morphology Nuclear Numbers Oncogenes Open Reading Frames Organ Organic solvent product Organism Organogenesis Outcome Palpable Pancreas Paper Pathologic Processes Pathway interactions Peptide Hydrolases Peptides Phagocytes Phagocytosis Pharmaceutical Preparations Phenotype Phosphatidylinositols Phosphatidylserines Phospholipase Phospholipase A2 Phospholipase D Phospholipids Phosphotransferases Physiological Physiology Planning Techniques Plasmids Play Polymerase Chain Reaction Population Portugal Positioning Attribute Postdoctoral Fellow Potassium Channel Predisposition Preparation Process Production Protein Dephosphorylation Protein Family Protein Overexpression Proteins Proto-Oncogene Proteins c-akt Prunella vulgaris Publishing RNA Interference Range Reaction Reactive Oxygen Species Reagent Recombinants Regulation Research Research Design Research Personnel Role Running Sampling Scheme Score Screening procedure Second Messenger Systems Sensory Shapes Signal Pathway Signal Transduction Simple Epithelium Site Skin Small Interfering RNA Sodium Solid Neoplasm Specificity Sphingomyelinase Sphingomyelins Sphingosine-1-Phosphate Receptor Staging Staining method Stains Standards of Weights and Measures Starvation Stimulus Stretching Surface Syndrome System Test Result Testing Therapeutic Agents Thin Layer Chromatography Thinking Time Tissues Training Transgenic Organisms Triglycerides Trypsin UV induced Ulcer United States National Institutes of Health Universities Utah Variant Viral Voltage-Gated Potassium Channel Whole Organism Work Yang Zebrafish abstracting annexin A5 anterograde transport base cancer cell career caspase-3 cell cortex cell type concept coping cytochrome c extracellular fly follow-up gastrointestinal system gene function human AMID protein in vivo inhibitor/antagonist innovation inorganic phosphate interest irradiation knock-down leukemia medical schools metaperiodate monolayer mouse model movie neoplastic cell neuroblast neuroepithelium novel oxidized lipid phospholipid scramblase prevent pro-apoptotic protein promoter rapid technique receptor reconstitution research study response rho second messenger separase small molecule sphingosine 1-phosphate sphingosine kinase stathmin stress-activated protein kinase 1 success sugar tissue culture tumor tumor progression ultraviolet ultraviolet irradiation unpublished works wound wound healing

项目摘要

I have discovered a mechanism called `extrusion', by which dying cells exit the epithelium without disrupting the barrier function of the layer. Here, a cell destined to die, signals its surrounding neighboring cells to form an intercellular actomyosin ring that contracts to squeeze the dying cell out. While stimuli that induce cell death (apoptosis) activate extrusion, we have also found that apoptosis and extrusion are not interdependent. This suggests that extrusion may remove cells from the epithelium in other circumstances. Signals that promote extrusion could, therefore, be used when cells leave the epithelium during developmental differentiation or initiation of tumor cell metastasis. Because most high-grade tumors have mutations in the apoptotic pathway, mutations that block apoptosis but not extrusion could enable a tumor cell to easily exit the epithelium and initiate its metastasis to other sites. Because metastasis is generally associated with cancer lethality, we believe that understanding the signalling that drives extrusion may be of utmost importance. We will also explore if extrusion might precede and induce apoptosis in overcrowded regions during normal homeostasis as a way of regulating cell numbers. Identifying the signals that trigger extrusion will be key to understanding the physiological functions that extrusion plays. We plan to identify the signalling pathway that initiates commitment of cell extrusion by investigating where this pathway bifurcates from the apoptotic pathway. We will also identify the downstream extra-cellular lipid signal that elicits extruding ring formation, as we think that this signal might provide a good molecular marker for extrusion. With these signals in hand, we will be able to test the function of extrusion in potential processes ranging from maintaining epithelial numbers and function to novel mechanisms for tumor formation and initiating tumor cell metastasis. To do so, we will extend our extrusion studies into whole zebrafish embryos.

我发现了一种称为“挤出”的机制，通过这种机制，垂死的细胞会退出上皮细胞而不破坏该层的屏障功能。在这里，注定要死亡的细胞发出信号包围邻近细胞，形成细胞间肌动球蛋白环，收缩挤压垂死的细胞出来了。虽然诱导细胞死亡（细胞凋亡）的刺激会激活挤压，但我们有还发现细胞凋亡和挤出并不是相互依赖的。这表明挤压在其他情况下可能会去除上皮细胞。促进挤压的信号因此，当细胞在发育分化期间离开上皮或肿瘤细胞转移的起始。因为大多数高级别肿瘤在细胞凋亡途径中，阻止细胞凋亡但不被挤出的突变可以使肿瘤细胞很容易离开上皮并开始转移到其他部位。因为转移是通常与癌症致死率相关，我们相信了解这一信号驱动挤压可能是最重要的。我们还将探讨挤压是否可能先于并在正常稳态期间诱导过度拥挤区域的细胞凋亡，作为调节的一种方式细胞数。识别触发挤压的信号将是理解挤压的关键挤压所发挥的生理功能。我们计划确定信号通路通过研究该途径从何处分叉来启动细胞挤出的承诺凋亡途径。我们还将确定引发的下游细胞外脂质信号挤压环形成，因为我们认为该信号可能提供良好的分子标记挤压。有了这些信号，我们将能够测试潜在的挤出功能从维持上皮数量和功能到新机制的过程肿瘤形成并引发肿瘤细胞转移。为此，我们将扩大挤压范围对整个斑马鱼胚胎的研究。