Molecular Pathogenesis of enterotoxigenic E. coli associated enteropathy

产肠毒素大肠杆菌相关性肠病的分子发病机制

• 批准号: 10656056
• 负责人: James Michael Fleckenstein
• 金额: $ 64.46万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656056
• 关键词: Acute Diarrhea; Address; Adult; Affect; Age; Architecture; Area; Atrophic; Attention; Automobile Driving; Biogenesis; Biological Assay; Biology; Brush Border; Cessation of life; Characteristics; Child; Cholera; Chromatin; Clinical; Country; Cyclic AMP; Cyclic GMP; Cyclic Nucleotides; Data; Dehydration; Developing Countries; Development; Diagnosis; Diarrhea; Disadvantaged; Disease; Enteral; Enterocytes; Epigenetic Process; Epithelial Cells; Epithelium; Escherichia coli Infections; Essential Genes; Exposure to; Fingers; Fostering; Functional disorder; Gene Expression; Genes; Genetic Transcription; Growth; Health; Hyperplasia; Impairment; In Vitro; Individual; Infection; Intellectual impairment; Intestines; Investigation; Ion Channel; Knowledge; Life; Link; Maintenance; Malnutrition; Mediating; Molecular; Morbidity - disease rate; Morphology; Nature; Nutrient; Oral Rehydration Therapy; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Play; Pneumonia; Process; Production; Proliferating; Protein Kinase; Resource-limited setting; Risk; Role; Sanitation; Second Messenger Systems; Signal Transduction; Site; Small Intestines; Sodium Chloride; Surface; Testing; Toxin; Toxoids; Transposase; Tropical sprue; Vaccination; Vaccines; Villus; Water; Work; base; beta catenin; cell type; cellular microvillus; diarrheal disease; enterotoxigenic Escherichia coli; human capital; in vivo; insight; intestinal epithelium; intestinal homeostasis; intestinal maturation; low and middle-income countries; meter; mortality; mortality risk; mouse model; neonatal mice; nutrient absorption; pathogen; prevent; protein activation; stem cell differentiation; transcriptome; wasting

Project Summary/Abstract This work focuses on enterotoxigenic Escherichia coli (ETEC), globally the most common bacterial cause of serious diarrheal illness. Originally identified more than 50 years ago as a cause of severe diarrheal illness in patients with clinical presentations indistinguishable from cholera, ETEC continue to threaten the lives of many children in poor regions of the world where sanitation and clean water remain limited. While deaths from diarrheal illness in low-middle income countries have declined, largely due to deployment of oral rehydration therapy, the tremendous morbidity associated with these illnesses remains completely unchecked. ETEC are closely linked to a condition known as environmental enteropathy or environmental enteric dysfunction (EED) that is complicated by sequelae of malnutrition, stunted growth, and intellectual impairment, robbing poor countries of badly needed human capital. Children with malnutrition are also at tremendously increased risk of dying from infectious diarrhea, pneumonia, and other common infections. In addition, ETEC have been linked to a centuries-old enigmatic disease, known as tropical sprue, that is typically diagnosed in adults with substantial repeated exposure to these pathogens. With EED it shares features of poor nutrient absorption, wasting, and alterations of small intestinal morphology. Much is known about of the molecular pathogenesis of acute diarrheal disease, with heat- labile (LT) and heat- stable (ST) toxins signaling through cAMP and cGMP second messenger pathways, respectively, to alter enterocyte ion channels that promote the net efflux of salt and water into the intestinal lumen. However, the biology underlying enteropathic changes to the small intestine and related sequelae are very poorly understood. Our recent studies indicate that ETEC toxins compromise cellular messages critical to the maintenance, biogenesis and function of small intestinal surfaces responsible for nutrient absorption. The current project will therefore address the following questions: · “What is the impact of ETEC and its individual toxins on the absorptive architecture of small intestine?” · “How does repeated ETEC infection affect the overall expression of genes that direct formation of surfaces needed for nutrient absorption?” · “Can we mitigate these effects by toxin-neutralizing vaccination?” Addressing these fundamental questions will fill important gaps in our understanding of the sequelae to ETEC infections, elucidate important features of the molecular pathogenesis of disease, and inform strategies to prevent illnesses that threaten millions of disadvantaged children worldwide.

项目概要/摘要 这项工作重点关注产肠毒素大肠杆菌 (ETEC)，它是全球范围内最常见的细菌性致病菌 50多年前最初被确定为严重腹泻病的原因。 临床表现与霍乱难以区分的患者中，ETEC 继续威胁着许多人的生命 世界贫困地区的儿童因卫生设施和清洁水仍然有限而死亡。 中低收入国家的腹泻病有所减少，这主要是由于口服补液的使用 治疗中，与这些疾病相关的巨大发病率仍然完全未被控制。 与环境性肠病或环境性肠功能障碍 (EED) 密切相关 营养不良、生长发育迟缓和智力障碍等后遗症使情况变得更加复杂，剥夺了穷人的生命 急需人力资本的国家，营养不良的儿童面临的风险也大大增加。 死于感染性腹泻、肺炎和其他常见感染此外，ETEC 也与此相关。 一种有数百年历史的神秘疾病，称为热带口炎性腹泻，通常在患有以下疾病的成年人中诊断出来： 大量反复接触这些病原体，会导致营养吸收不良， 消耗和小肠形态的改变。 人们对急性腹泻病的分子发病机制了解很多，其中包括不耐热（LT）和耐热性腹泻。 稳定 (ST) 毒素分别通过 cAMP 和 cGMP 第二信使途径发出信号，以改变 促进盐和水净流入肠腔的肠上皮细胞离子通道。 小肠肠病变化及相关后遗症的生物学基础非常差 我们最近的研究表明，ETEC 毒素会损害对人体至关重要的细胞信息。 负责营养吸收的小肠表面的维持、生物发生和功能。 因此，当前的项目将解决以下问题： · “ETEC 及其各自的毒素对小肠的吸收结构有什么影响？” · “重复的 ETEC 感染如何影响指导形成的基因的整体表达 吸收养分所需的表面？” · “我们可以通过毒素中和疫苗接种来减轻这些影响吗？” 解决这些基本问题将填补我们对 ETEC 后遗症理解的重要空白 感染，阐明疾病分子发病机制的重要特征，并提供治疗策略 防止威胁全世界数百万弱势儿童的威胁。