Translational Approaches to Develop Drug Therapy for Diarrhea

描述(申请人提供)：急性和慢性腹泻疾病是导致发展中国家婴儿死亡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，在美国，它们是发病率的第二大原因，在美国，它们是巨大的经济负担。由于缺乏批准的、安全和高效的止泻药物，NIH在2011年9月举行的一次单一主题会议上得出结论，开发治疗所有形式的腹泻的药物疗法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，这是由于在有或没有刺激Cl-分泌的情况下抑制了Na+的吸收。相反，缺乏关于主要离子转运蛋白在正常人类肠道中的分布和表达程度、这种变化如何随年龄变化以及转运蛋白活性和表达如何随着各种腹泻而变化的信息。R24代表了来自三个机构的5名主要研究人员的合作努力，他们都对肠上皮运输及其调控有主要的研究兴趣，但他们带来了几个不同但互补的研究领域的专业知识，这些领域是实现本项目目标所需的。通过这种方式，我们建议为当前和未来止泻药的开发提供所需的科学基础。这个项目的目的是：1.利用存档的人类肠道、小鼠肠道和人类肠道，开发潜在的止泻药物靶标在健康对照和腹泻中的肠道表达目录；标准化小鼠小肠和人类肠道的模型腹泻；以及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。II.确定腹泻模型中特定的Na+吸收转运体和Cl-分泌转运体的功能变化及其发生的机制，包括新发现的止泻药物的作用。确定新型抗分泌和促吸收治疗药物在体内和体外腹泻模型中的疗效。NHE3刺激物的高通量筛选。

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.