Regulation of secretory diarrhea by ER-PM junction signaling

ER-PM 连接信号传导调节分泌性腹泻

基本信息

批准号：
9762913
负责人：
Alexandra Chang-Graham
金额：
$ 4.13万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762913
关键词：
Address Age Apical Binding Biochemical Biological Models Biosensor Calcium Cell membrane Cell physiology Cells Child Chloride Channels Chlorides Cholera Toxin Cognitive Complex Constipation Cyclic AMP Cyclic GMP Cyclic Nucleotides Cystic Fibrosis Transmembrane Conductance Regulator Data Dehydration Development Developmental Delay Disorders Diarrhea Dysentery Endoplasmic Reticulum Enteral Epithelial Cells Fellowship Fluids and Secretions Functional disorder Future Gastrointestinal Physiology Gastrointestinal tract structure Genetic Engineering Goals Health Homeostasis Human Human Engineering Imaging Techniques Intestines Ion Channel Knowledge Life Mediator of activation protein Microscopy Modeling Molecular Morbidity - disease rate Mus Nonstructural Protein Norovirus Oral Rehydration Therapy Pharmacology Physicians Play Process Proteins Regulation Research Research Project Grants Role Rotavirus Rotavirus Infections STIM1 gene Scientific Advances and Accomplishments Scientist Severity of illness Signal Pathway Signal Transduction Small Intestines Structure Testing Training Vaccines Virus base clinically relevant diarrheal disease extracellular global health inhibitor/antagonist insight knock-down live cell imaging mortality mouse model multidisciplinary overexpression pathogen pathogenic bacteria protein complex recruit sensor skills small hairpin RNA tool

Address Age Apical Binding Biochemical Biological Models Biosensor Calcium Cell membrane Cell physiology Cells Child Chloride Channels Chlorides Cholera Toxin Cognitive Complex Constipation Cyclic AMP Cyclic GMP Cyclic Nucleotides Cystic Fibrosis Transmembrane Conductance Regulator Data Dehydration Development Developmental Delay Disorders Diarrhea Dysentery Endoplasmic Reticulum Enteral Epithelial Cells Fellowship Fluids and Secretions Functional disorder Future Gastrointestinal Physiology Gastrointestinal tract structure Genetic Engineering Goals Health Homeostasis Human Human Engineering Imaging Techniques Intestines Ion Channel Knowledge Life Mediator of activation protein Microscopy Modeling Molecular Morbidity - disease rate Mus Nonstructural Protein Norovirus Oral Rehydration Therapy Pharmacology Physicians Play Process Proteins Regulation Research Research Project Grants Role Rotavirus Rotavirus Infections STIM1 gene Scientific Advances and Accomplishments Scientist Severity of illness Signal Pathway Signal Transduction Small Intestines Structure Testing Training Vaccines Virus base clinically relevant diarrheal disease extracellular global health inhibitor/antagonist insight knock-down live cell imaging mortality mouse model multidisciplinary overexpression pathogen pathogenic bacteria protein complex recruit sensor skills small hairpin RNA tool

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项目摘要

PROJECT SUMMARY Secretory diarrhea is a major cause of morbidity and mortality in children resulting from the overstimulation of chloride (Cl-) channels in intestinal epithelial cells (IECs) that leads to overwhelming fluid secretion and life- threatening dehydration. These Cl- channels are regulated by cyclic nucleotides (cAMP and cGMP) and calcium (Ca2+) signaling pathways, but there are gaps in knowledge in how pathogens, such as rotavirus (RV), cause diarrhea through elevation of cytosolic Ca2+ ([Ca2+]c). RV persistently activates stromal interaction molecule 1 (STIM1) in infected cells, which in turn activates processes for extracellular Ca2+ entry at endoplasmic reticulum-plasma membrane (ER-PM) junctions. Activated STIM1 causes formation of ER-PM junction protein complexes that regulate Ca2+ and cAMP signaling and potentially the activation of Ca2+- activated and cAMP-activated chloride channels. Understanding the identity and activation of Cl- channels in RV infection is significant for advancing scientific knowledge of fluid secretion in the GI tract as well as future development of anti-secretory therapies to treat infectious and functional diarrhea. Thus the objective of this research is to identify the Cl- channels activated during RV infection and the regulatory role of activated STIM1 in ER-PM junctional complexes in their activation. I hypothesize that persistent activation of STIM1 stimulates the activation of Ca2+- and cAMP-dependent Cl- channels for RV-induced diarrhea. Using human intestinal enteroids (HIEs) genetically modified with biosensors as a model of IECs and a mouse model of RV diarrhea, I propose [1] to identify the Cl- channels activated during RV infection and [2] to determine the dynamic composition of ER-PM junctions with STIM1 activation in RV-infected IECs. Results from the proposed project will significantly advance our current understanding of molecular mechanisms of Cl- secretion in IECs, which can be extended to study other enteric viruses and bacterial pathogens. These findings will provide new insights into the regulatory roles of ER-PM junctions in the specialization of cell functions.

项目摘要分泌性腹泻是因过度刺激而导致儿童发病和死亡率的主要原因肠上皮细胞（IEC）中的氯化物（Cl-）通道，导致压倒性的液体分泌和生命 - 威胁脱水。这些Cl-通道受环核苷酸（CAMP和CGMP）和钙（Ca2+）信号通路，但是在病原体（例如轮状病毒）（RV），通过胞质Ca2+（[Ca2+] C）的升高引起腹泻。 RV持续激活基质相互作用感染细胞中的分子1（imt1），进而激活细胞外Ca2+进入的过程内质网 - 铂膜（ER-PM）连接。激活的stim1导致ER-PM的形成调节Ca2+和CAMP信号的连接蛋白复合物，并可能激活Ca2+ - 激活和营地活化的氯化物通道。了解Cl-通道的身份和激活 RV感染对于促进胃肠道和未来的流体分泌的科学知识很重要开发抗分泌疗法以治疗传染性和功能性腹泻。因此，这个目的研究是确定在RV感染过程中激活的CL通道和激活的STIM1的调节作用在ER-PM连接络合物中的激活中。我假设STIM1的持续激活刺激RV诱导的腹泻的Ca2+ - 和CAMP依赖性Cl-通道的激活。使用人类肠内肠托动物（HIE）用生物传感器作为IEC和小鼠模型进行了基因修饰我建议[1]识别RV感染过程中激活的CL通道，并确定[2] ER-PM连接在RV感染的IEC中激活ER-PM连接的动态组成。结果拟议的项目将大大提高我们当前对Cl-分泌机制的理解在IEC中，可以扩展以研究其他肠道病毒和细菌病原体。这些发现会提供有关ER-PM连接在细胞功能专业化中的调节作用的新见解。