Translational Approaches to Develop Drug Therapy for Diarrhea

开发腹泻药物治疗的转化方法

基本信息

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
项目类别：
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

项目摘要

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.

急性和慢性腹泻病是导致死亡率和发病率的主要原因它们是发展中国家婴儿死亡的第二大常见原因在美国，它们的发病率构成了巨大的经济负担。缺乏批准，安全高效的止泻药，NIH 单一主题会议于 9/2011 举行得出的结论是，开发治疗所有形式腹泻的药物疗法具有很高的效果研究重点是减少腹泻的持续时间和数量。所需要的我们认为，腹泻药物开发所缺乏的信息并不存在。了解腹泻的病理生理学是由于抑制 Na+ 吸收所致或不刺激Cl-分泌。相反，这是缺乏有关正常人中主要离子转运蛋白的分布和表达程度肠道，它如何随年龄变化，以及转运蛋白活性和表达如何变化伴有各种腹泻。 R24 代表了 5 位主要研究人员的共同努力来自三个机构，他们的主要研究兴趣都是肠上皮运输及其监管，但他们带来了几个不同但互补的专业知识实现该项目目标所需的研究领域。这样我们提出为当前和未来的发展提供所需的科学基础止泻药。该项目的目标是 I. 开发肠道目录使用健康对照和腹泻中潜在抗腹泻药物靶标的表达存档的人类肠道、小鼠肠道和人类肠类；标准化模型小鼠小肠和人肠样腹泻；并进行表型筛选使用人类肠类来识别治疗腹泻模型的独特药物。二.决定腹泻中特定 Na+ 吸收性和 Cl- 分泌性转运蛋白的功能变化模型及其发生的机制，包括新发现的影响止泻药。三．确定新型抗分泌和促吸收药物的功效体内和离体腹泻模型的治疗。 NHE3 的高通量筛选刺激器。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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