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：
9298626
负责人：
MARK DONOWITZ
金额：
$ 176.41万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9298626
关键词：
Acute Address Affect Age Agreement Animal Model Antidiarrheals Apical Archives Area Biopsy CLCA2 gene Carrier Proteins Catalogs Cholera Toxin Chronic 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 Microscopy 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 drug candidate drug development efficacy testing high throughput screening illness length in vivo interest monolayer mortality mouse model novel novel therapeutics protein B protein expression protein transport public health relevance small molecule symposium therapy development tool translational approach two-photon

项目摘要

DESCRIPTION (provided by applicant): 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 th efficacy of novel anti-secretory and pro-absorptive therapeutics in in vivo and ex vivo diarrheal models. High throughput screen for NHE3 stimulators.

描述（由申请人提供）：急性和慢性腹泻疾病是发展中国家死亡率和发病率的主要原因，在这些国家，它们是婴儿死亡的第二大常见原因，在美国，急性和慢性腹泻疾病是造成巨大经济负担的第二大发病原因。由于缺乏经批准、安全且高效的抗腹泻药物，NIH 在 2011 年 9 月举行的单一主题会议得出结论，开发治疗所有形式腹泻的药物疗法具有高度的研究优先权，目标是减少腹泻的持续时间和数量。我们对腹泻病理生理学的理解并不存在腹泻药物开发所需的信息，因为在刺激或不刺激 Cl- 分泌的情况下抑制 Na+ 吸收。相反，缺乏有关正常人肠道中主要离子转运蛋白的分布和表达程度、其如何随年龄变化以及转运蛋白活性和表达如何随各种腹泻而变化的信息。该 R24 代表了来自三个机构的 5 名主要研究人员的合作成果，他们的主要研究兴趣都是肠上皮运输及其调节，但他们带来了实现本研究目标所需的几个不同但互补的研究领域的专业知识。项目。通过这种方式，我们建议为当前和未来抗腹泻药物的开发提供所需的科学基础。该项目的目标是 I. 使用存档的人肠、小鼠肠和人肠类，开发健康对照和腹泻中潜在抗腹泻药物靶标的肠道表达目录；标准化小鼠小肠和人肠样腹泻模型；并使用人肠类进行表型筛选，以确定治疗腹泻模型的独特药物。二.确定腹泻模型中特定 Na+ 吸收性和 Cl- 分泌性转运蛋白的功能变化及其发生机制，包括新鉴定的抗腹泻药物的作用。三．确定新型抗分泌和促吸收疗法在体内和离体腹泻模型中的功效。 NHE3 刺激器的高通量筛选。