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.

急性和慢性牙周病是导致死亡率和发病率的主要因素， 在发展中国家，这是婴儿死亡的第二大最常见原因， 在美国，它们是一个巨大的经济负担。缺乏认可， 安全高效的抗真菌药物，2011年9月举行的NIH单一主题会议 结论是，开发治疗各种形式腹泻的药物治疗具有很高的价值， 研究的重点是减少腹泻的持续时间和数量。所需的 在我们的研究中， 了解腹泻的病理生理学是由于抑制Na+吸收， 或不刺激Cl-分泌。相反，它缺乏关于 正常人主要离子转运蛋白的分布和表达程度 肠道，这是如何随着年龄的变化，以及转运蛋白的活性和表达如何变化 各种各样的兰花。这个R24代表了5个主要研究者的合作努力 来自三个机构，他们都对肠上皮细胞有主要的研究兴趣， 运输及其监管，但谁带来的专业知识，在几个不同的，但互补的 为实现本项目的目标所需的研究领域。这样我们 建议为当前和未来的发展提供所需的科学基础， 抗疟疾药这个项目的目的是我。开发一个肠道疾病目录 在健康对照和大肠杆菌中表达潜在的抗结肠炎药物靶点， 人肠、小鼠肠和人肠样组织;标准化模型 小鼠小肠和人类肠上皮细胞中的大肠杆菌;并进行表型筛选 使用人类肠类来鉴定治疗腹泻模型的独特药物。二.确定 腹泻时特异性Na+吸收和Cl-分泌转运体功能的变化 模式和机制，其中发生，包括新确定的影响， 抗疟疾药三.确定新型抗分泌和促吸收药物的疗效 在体内和离体结肠炎模型中的治疗剂。NHE 3的高通量筛选 刺激物。

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