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Mechanisms of Inhibition of Intestinal SERT by EPEC Infection.

EPEC 感染抑制肠道 SERT 的机制。

基本信息

批准号：
8487402
负责人：
Ravinder K Gill
金额：
$ 6.08万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8487402
关键词：
5 year old Acute Applications Grants Bacteria Cause of Death Cell Count Cell model Cessation of life Child Childhood Complex Diarrhea Disease Drug Targeting Enteral Enterochromaffin Cells Enterotoxins Epithelial Epithelial Cells Escherichia coli Infections Event Functional disorder Goals Health Homeostasis In Vitro Infant Infantile Diarrhea Infection Infectious Agent Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Intestines Ions Irritable Bowel Syndrome Liquid substance Microbe Modality Modeling Molecular Morbidity - disease rate Mus Oral Rehydration Therapy Outcome Study Pathogenesis Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Physiological Process Protein Dephosphorylation Protein Tyrosine Phosphatase Proteins Regulation Research Role Serine Serotonin Signal Transduction Therapeutic Threonine Toxin Type III Secretion System Pathway absorption base cell motility enteropathogenic Escherichia coli foodborne foodborne pathogen gastrointestinal ileum in vivo in vivo Model insight killings microbial host mortality mouse model mutant novel novel strategies pathogen prevent response serotonin transporter uptake

项目摘要

DESCRIPTION (provided by applicant): Diarrheal diseases caused by infectious agents continue to pose a serious health problem, especially in infants. It is, therefore, necessary to develop novel efficacious drugs to treat diarrhea. Intestinal serotonin transporter (SERT), involved in regulation of luminal 5-HT availability, is an important candidate to target because of its implications in several diarrheal disorders. The proposed studies are focused at examining the role of serotonin transporter (SERT) in the pathophysiology of diarrhea associated with infection by an important food-borne pathogen, Enteropathogenic E. coli (EPEC). Because of the lack of a known toxin, pathophysiology of EPEC-induced early diarrhea remained elusive for many years. Emerging studies have revealed that mechanism(s) underlying EPEC associated diarrhea are multi-factorial. Our recent studies showed that EPEC inhibits SERT in the intestinal epithelial cells via activation of protein tyrosine phosphatases. However, the detailed mechanisms underlying EPEC induced inhibition of SERT are not known. We hypothesize that EPEC induced signaling events alter SERT phosphorylation levels to cause its inhibition that may contribute to associated diarrhea. The present studies will systematically examine the effects of EPEC infection on SERT utilizing both in vitro and in vivo models. Studies proposed in Specific Aim 1 will identify the specific serine/threonine/tyrosine phosphatases involved in SERT modulation post-infection and will identify the structural domains that harbor SERT phosphorylation site(s). Specific Aim 2 will critically elucidate the mechanisms of acute inhibitio of SERT in response to EPEC infection by assessing the role of cellular phosphatases in the native mouse ileum. In addition, the effect of phosphatases on serotonergic machinery (5-HT synthesis and release) will be examined to model the net impact of EPEC infection in complex native intestine. Overall, the proposed studies will help provide valuable insights into the host-microbial epithelial interaction underlying pathophysiology of EPEC- associated diarrhea as well as will increase our understanding of phosphorylation/dephosphorylation mechanisms governing SERT activity under physiological and pathophysiological conditions.

描述（由申请人提供）：由传染性病原体引起的腹泻病继续构成严重的健康问题，特别是对婴儿。因此，有必要开发新的有效药物来治疗腹泻。肠道5-羟色胺转运蛋白（SERT）参与调节肠道5-羟色胺的可用性，是一个重要的候选靶点，因为