Translational Approaches to Develop Drug Therapy for Diarrhea

开发腹泻药物治疗的转化方法

• 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
• 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

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，急性和慢性腹泻病是婴儿死亡的第二大常见原因，在美国，急性和慢性腹泻病是发病率的主要原因，在美国，急性和慢性腹泻病是巨大的经济负担。由于缺乏经批准的、安全和高效的抗腹泻药物，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疗法具有高度的研究优先权，其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，我们认为由于在刺激或不刺激Cl-分泌的情况下抑制Na+吸收而缺乏腹泻药物开发所需的信息。相反，它缺乏关于正常人肠道中主要离子转运蛋白的分布和表达程度的信息，这如何随年龄变化，以及转运蛋白的活性和表达如何随各种肠道而变化。这个R24代表了来自三个机构的5名主要研究人员的合作努力，他们都对肠上皮细胞转运及其调节有主要研究兴趣，但他们带来了几个不同但互补的研究领域的专业知识，这些领域是解决这个项目的目标所必需的。通过这种方式，我们建议为当前和未来的抗真菌药物开发提供所需的科学基础。这个项目的目的是我。使用存档的人肠、小鼠肠和人肠样物质，开发健康对照和腹泻中潜在抗腹泻药物靶标的肠表达目录;标准化小鼠小肠和人肠样物质中的模型腹泻;并使用人肠样物质进行表型筛选，以鉴定治疗腹泻模型的独特药物。二.确定腹泻模型中特异性Na+吸收和Cl-分泌转运蛋白的功能变化及其发生机制，包括新发现的抗腹泻药物的作用。三.在体内和离体结肠炎模型中确定新型抗分泌和促吸收治疗剂的功效。NHE 3刺激物的高通量筛选。