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.

急慢性腹泻病是#年死亡率和发病率的主要因素。 在发展中国家，它们是婴儿死亡的第二大原因， 到美国的发病率，在那里他们代表着巨大的经济负担。缺乏批准， 安全高效的止泻药，美国国立卫生研究院2011年9月举行的单一主题会议 结论是药物疗法的发展对治疗各种形式的腹泻都有很高的 优先研究，目标是减少腹泻的持续时间和数量。所需的 缺乏腹泻药物开发的信息在我们的 对Na+吸收受抑所致腹泻的病理生理学认识 或无氯离子分泌刺激。相反，这是因为缺乏关于 主要离子转运蛋白在正常人体内的分布和表达程度 肠道，这种变化如何随着年龄的变化，以及转运蛋白的活动和表达如何变化 伴随着各种腹泻。R24代表了5个主要调查人员的协作努力 来自三个机构，他们都对肠道上皮细胞有主要的研究兴趣 运输及其监管，但谁带来了几个不同但互补的专业知识 为实现该项目的目标所需的研究领域。通过这种方式，我们 建议为当前和未来的发展提供所需的科学基础 止泻药。这个项目的目的是为了。开发一个肠道的目录。 潜在的止泻药物靶点在健康对照和腹泻患者中的表达 存档的人体肠道、小鼠肠道和人体肠类；标准化模型 小鼠小肠和人类肠道的腹泻；并进行表型筛选 使用人类肠样来识别治疗腹泻模型的独特药物。二、确定 腹泻时特异性钠离子吸收转运体和氯离子分泌转运体功能的变化 模型及其发生机制，包括新确定的 止泻药。三、测定新型抗分泌剂和促吸收药的疗效 体内和体外腹泻模型的治疗。适用于NHE3的高通量屏幕 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