Translational Approaches to Develop Drug Therapy for Diarrhea

描述（由申请人提供）：急性和慢性腹泻病是发展中国家死亡率和发病率的主要原因，在发展中国家，腹泻病是婴儿死亡率的第二大常见原因，在美国，腹泻病是一个巨大的经济负担。由于缺乏被批准的、安全的、高效的抗腹泻药物，2011年9月举行的NIH单一主题会议得出结论，开发治疗所有形式腹泻的药物治疗具有高度的研究重点，目标是减少腹泻的持续时间和数量。在我们对腹泻的病理生理学的理解中，缺乏腹泻药物开发所需的信息，这是由于有或没有刺激Cl-分泌抑制Na+吸收引起的。相反，缺乏关于正常人类肠道中主要离子转运蛋白的分布和表达程度的信息，这种情况如何随年龄变化，以及转运蛋白的活性和表达如何随各种腹泻而变化。该R24是来自三家机构的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控，但他们在几个不同但互补的研究领域带来了专业知识，这些领域需要实现本项目的目标。从而为当前和未来抗腹泻药物的开发提供必要的科学依据。本项目的目的是：1 .利用已存档的人肠、小鼠肠和人肠，编制健康对照和腹泻中潜在抗腹泻药物靶点的肠道表达目录；小鼠小肠和人肠道腹泻模型的标准化；并使用人类肠道进行表型筛选，以确定治疗腹泻模型的独特药物。2。确定腹泻模型中特定Na+吸收和Cl-分泌转运体功能的变化及其发生的机制，包括新发现的抗腹泻药物的作用。3。测定新型抗分泌和促吸收药物在体内和体外腹泻模型中的疗效。NHE3刺激器高通量筛。

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.