Translational Approaches to Develop Drug Therapy for Diarrhea

开发腹泻药物治疗的转化方法

• 批准号: 9892562
• 负责人: MARK DONOWITZ
• 金额: $ 7.97万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892562
• 关键词: Acute Diarrhea; Address; Affect; Age; Agreement; Animal Model; Antidiarrheals; Apical; Archives; Area; Biopsy; CLCA2 gene; Carrier Proteins; Catalogs; Cholera Toxin; Chronic diarrhea; Collaborations; Cyst; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Developing Countries; Development; Diagnostic; Diarrhea; Disease; Drug Targeting; Drug effect disorder; Economic Burden; Elderly; Electrolytes; Electrophysiology (science); Enterocytes; Epithelial; Fluids and Secretions; Functional disorder; Future; Goals; Health; Human; Individual; Infant; Infant Mortality; Inflammatory; Institution; Intestinal Absorption; Intestinal Secretions; Intestines; Ion Transport; Ions; Life; Measures; Mediator of activation protein; Membrane Transport Proteins; Microfluidics; Modeling; Monoclonal Antibody R24; Morbidity - disease rate; Mus; Natural Products; Patients; Pattern; Peptides; Perfusion; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Problem Solving; Process; Property; Regulation; Research; Research Personnel; Research Priority; Rotavirus; Series; Site; Small Intestines; Standardization; TNF gene; Testing; Therapeutic; Therapeutic Agents; Treatment Efficacy; United States National Institutes of Health; Viral; Water; Work; absorption; base; clinical development; diarrheal disease; drug candidate; drug development; efficacy testing; high throughput screening; human model; illness length; in vivo; interest; monolayer; mortality; mouse model; novel; novel therapeutics; protein B; protein expression; protein transport; small molecule; symposium; therapy development; tool; translational approach; two photon microscopy

Acute and chronic diarrheal diseases are major contributors to mortality and morbidity in developing countries where they are the second most frequent cause of infant mortality and to morbidity in the USA where they represent a huge economic burden. Lacking approved, safe and highly effective anti-diarrheal drugs, a NIH Single Topic Conference held 9/2011 concluded that development of drug therapy to treat all forms of diarrhea has a high research priority with the goal of reducing the duration and amount of diarrhea. The needed information that was lacking for diarrheal drug development was not felt to be in our understanding of the pathophysiology of diarrhea as due to inhibition of Na+ absorption with or without stimulation of Cl- secretion. Rather it was lack of information about the distribution and extent of expression of major ion transport proteins in the normal human intestine, how this changes with age, and how transporter activity and expression changes with various diarrheas. This R24 represents a collaborative effort of 5 principle investigators from three institutions all of whom have a primary research interest in intestinal epithelial transport and its regulation, but who bring expertise in several different but complementary areas of research which are needed to address the aims of this project. In this way we propose to provide the scientific underpinning needed for current and future development of anti-diarrheal drugs. The Aims of this project are to I. Develop a catalogue of the intestinal expression of potential anti-diarrheal drug targets in healthy controls and diarrheas using archived human intestine, mouse intestine and human enteroids; standardize model diarrheas in mouse small intestine and human enteroids; and perform a phenotypic screen using human enteroids to identify unique drugs to treat the diarrhea models. II. Determine changes in function of specific Na+ absorptive and Cl- secretory transporters in the diarrhea models and the mechanisms by which they occur, including effects of the newly identified anti-diarrheal drugs. III. Determine the efficacy of novel anti-secretory and pro-absorptive therapeutics in in vivo and ex vivo diarrheal models. High throughput screen for NHE3 stimulators.

急性和慢性腹泻疾病是导致死亡率和发病率的主要因素 发展中国家是婴儿死亡率第二大的原因 在美国的发病率上，他们代表了巨大的经济负担。缺乏批准， 安全且高效的抗diarheal药物，NIH单一主题会议9/2011举行 结论是，治疗所有形式腹泻的药物疗法的开发具有很高的 研究优先级，目的是减少腹泻的持续时间和量。需要的 没有腹泻药物开发缺乏的信息在我们的 由于抑制了Na+吸收，了解腹泻的病理生理学 或不刺激cl-分泌。而是缺乏有关 正常人中主要离子转运蛋白的表达分布和程度 肠道，随着年龄的变化以及转运蛋白的活性和表达如何变化 有各种腹泻。该R24代表了5个主要研究人员的合作努力 从三个机构中，所有这些机构对肠上皮都有主要的研究兴趣 运输及其法规，但他们带来了几种不同但互补的专业知识 需要解决该项目目标所需的研究领域。这样我们 建议提供当前和未来发展所需的科学基础 抗diarheal药物。该项目的目的是I.开发肠道目录 在健康对照中表达潜在的抗diarheal药物靶标在腹泻中的表达 存档的人类肠道，小鼠肠和人肠肠；标准化模型 小鼠小肠和人肠to中的腹泻；并执行表型屏幕 使用人肠to以识别独特的药物来治疗腹泻模型。 ii。决定 腹泻中特定Na+吸收性和分泌转运蛋白的功能变化 模型及其发生的机制，包括新确定的影响 抗diarheal药物。 iii。确定新型的反分泌和促进性的功效 体内和离体腹泻模型中的治疗剂。 NHE3的高吞吐量屏幕 刺激器。

项目成果

A Novel Peptide Prevents Enterotoxin- and Inflammation-Induced Intestinal Fluid Secretion by Stimulating Sodium-Hydrogen Exchanger 3 Activity.

一种新型肽通过刺激钠氢交换器 3 活性来防止肠毒素和炎症引起的肠液分泌。

• DOI: 10.1053/j.gastro.2023.06.028
• 发表时间: 2023
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Zachos,NicholasC;Vaughan,Hannah;Sarker,Rafiquel;Est-Witte,Savannah;Chakraborty,Molee;Baetz,NicholasW;Yu,Hongzhe;Yarov-Yarovoy,Vladimir;McNamara,George;Green,JordanJ;Tse,Chung-Ming;Donowitz,Mark
• 通讯作者: Donowitz,Mark