Sodium Transport Inhibitors for Hypertension and Cystic Fibrosis

钠转运抑制剂治疗高血压和囊性纤维化

基本信息

批准号：
7612426
负责人：
Erik Mills Schwiebert
金额：
$ 10万
依托单位：
DISCOVERYBIOMED, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-25 至 2009-09-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7612426
关键词：
Acute Affect Attenuated Biological Assay Biological Factors Blood Pressure Blood Vessels Carrier Proteins Cell model Cell physiology Cell surface Cells Characteristics Child Childhood Chloride Ion Chlorides Chronic Kidney Failure Commercial Sources Cystic Fibrosis Dehydration Depth Development Disease Doctor of Philosophy Duct (organ) structure Ductal Epithelium Epithelial Epithelial Cells Equilibrium Eye Functional disorder Genes Goals Housing Human Hydration status Hypertension Inherited Kidney Knock-out Libraries Ligands Liquid substance Lung Lung diseases Marketing Measures Methods Molecular Molecular Bank Molecular Target Mucous body substance Nephrons Osmolalities Patients Phase Physiological Physiology Plant Roots Plasma Population Process Proteins Public Health Pulmonary Cystic Fibrosis Research Resistance Screening procedure Small Business Funding Mechanisms Small Business Innovation Research Grant Sodium Sodium Chloride Surface Systemic disease Testing Therapeutic Time Up-Regulation Vascular Diseases Vascular System Work absorption collecting tubule structure cystic fibrosis airway cystic fibrosis airway epithelia cystic fibrosis mouse design drug discovery epithelial Na+ channel familial hypertension fighting gastrointestinal system human disease in vivo inhibitor/antagonist kidney vascular structure monolayer mortality mouse model novel novel therapeutics programs research study respiratory serum sodium transport inhibitor small molecule transport inhibitor voltage young adult

项目摘要

DESCRIPTION (provided by applicant): Sodium Transport Inhibitors for Hypertension and Cystic Fibrosis Scientific Summary Description Hypertension is a confounding multifactorial disorder that affects millions of patients worldwide. Cystic fibrosis (CF) is an inherited disease of the pulmonary and gastrointestinal systems that presents in pediatric and young adult populations. What do hypertension and cystic fibrosis (CF) have in common? The central common feature is enhanced absorptive sodium (Na+) transport. Heightened Na+ transport across renal epithelial cells in the latter segments of the nephron of the kidney drives hypertension; accelerated salt absorption across respiratory epithelial cells causes airway surface dehydration in CF. A cardinal rule in vascular physiology is that 2 x plasma Na+ concentration equates with normal plasma osmolality and sets plasma volume and blood pressure, the physiological parameter that is elevated in hypertension. The balance of chloride secretion and Na+ absorption sets the depth of hydration of the ciliated layer on the airway epithelial cell surface. A recent mouse model of CF where an epithelial Na+ channel (ENaC) is conditionally upregulated has proven to be the best mouse model mimicking CF lung disease. Knockouts of the CF gene itself have not been as successful. DiscoveryBioMed, Inc. (DBM) has developed a novel and electrical high-throughput molecular screening format where Na+ transport inhibitors (NTIs) will be discovered via assessment of Na+ transport across polarized epithelial cell models of the renal collecting duct and the CF airway. Na+ transport proteins are the shared molecular target for both disease platforms. ENaC and other epithelial Na+-permeable channels and transporters are notoriously difficult to study outside of a polarized epithelial cell format. Because of this fact, DBM has developed this novel electrical HTS method to screen panels of molecular libraries on polarized epithelial cell models from the kidney (to find potential therapeutics to fight hypertension) and the airways (to find potential therapeutics to fight CF). DBM holds a core principle that drug discovery is accelerated if the screening is performed on an epithelial cell model of disease that maintains in vivo characteristics. DBM has found hit compounds through its novel electrical HTS bioassay that are inhibitors of Na+ transport in kidney collecting duct epithelia, CF airway epithelia or both. The central hypothesis of this Phase 1 SBIR proposal is that novel NTIs will be found that will be developed into viable therapeutics for both hypertension as a large market disease and CF as a niche market disease. This Phase 1 SBIR program has 2 milestones. Milestone 1 aims to select, perfect and optimize the use of polarized kidney collecting duct and airway epithelial cell models for electrical HTS for Na+ transport inhibitors. Milestone 2 is to complete a pilot screen of 15,000 compounds and to validate, compare and contrast the hit compounds found from the pilot electrical screen with additional Na+ transport-relevant assays. The over-arching goal of this work is to identify small molecules that may attenuate enhanced Na+ transport that fuels hypertension, CF or both human diseases, compounds that may eventually be transformed into new therapeutics for these diseases. PUBLIC HEALTH RELEVANCE: Hypertension is a debilitating and common disorder that often takes root in the kidney and the vascular system. Upregulation of the activity of proteins in cells that regulate plasma salt and blood pressure, often in the kidney, are routinely involved in renal hypertensive disorders, chronic kidney diseases with hypertension, and vascular diseases. Cystic fibrosis is a disease of children and young adults that causes mortality due to its progressive and debilitating lung disease. Accelerated absorption of salt dehydrates the airways and cause sticky mucus accumulation that eventually obstructs airflow leading to pulmonary decline. Our company seeks to find inhibitors of elevated salt transport that confound and accelerate the progression of multiple human diseases.

描述（由申请人提供）：高血压和囊性纤维化科学摘要描述高血压高血压的钠转运抑制剂是一种混杂的多因素疾病，影响了全球数百万患者。囊性纤维化（CF）是呈现在儿科和年轻人种群中的肺和胃肠道系统的遗传疾病。高血压和囊性纤维化（CF）有什么共同点？中心共同特征是增强的吸收钠（Na+）转运。在肾脏肾脏的后一个部分中，Na+跨肾上皮细胞的转运增加了高血压。跨呼吸道上皮细胞的加速盐吸收会导致CF中气道表面脱水。血管生理学中的基本规则是，2 x等离子体Na+浓度等同于正常的血浆渗透压，并设置血浆体积和血压，这是高血压升高的生理参数。氯化物分泌和Na+吸收的平衡使气道上皮细胞表面上纤毛层的水合深度。最近，有条件上调的上皮Na+通道（ENAC）的CF小鼠模型已被证明是模仿CF肺部疾病的最佳小鼠模型。 CF基因本身的敲除并没有那么成功。 DiscoveryBiomed，Inc。（DBM）开发了一种新型和电气的高通量分子筛选格式，其中Na+转运抑制剂（NTI）将通过评估Na+转运跨过肾脏收集导管和CF Airway的NA+转运。 Na+转运蛋白是两个疾病平台的共享分子靶标。众所周知，ENAC和其他上皮Na+可渗透通道和转运蛋白很难在极化的上皮细胞格式之外进行研究。由于这一事实，DBM开发了这种新型的电气HTS方法，以从肾脏的极化上皮细胞模型上筛选分子库的面板（以找到与高血压作斗争的潜在治疗剂）和呼吸道（以找到与CF对抗CF的潜在疗法）。 DBM持有一个核心原则，即如果在维持体内特征的疾病上皮细胞模型上进行筛查，则可以加速药物发现。 DBM通过其新型的电气HTS生物测定方法发现了命中型化合物，它们是Na+转运的抑制剂，在肾脏收集管道上皮，CF气道上皮或两者兼而有之。这一阶段1 SBIR提案的中心假设是，将发现新的NTI将被发现为高血压作为大型市场疾病的可行治疗剂，又是CF作为利基市场疾病。该第1阶段SBIR计划具有2个里程碑。 Milestone 1旨在选择，完善和优化用于NA+传输抑制剂电HTS的极化肾脏收集管道和气道上皮细胞模型。 Milestone 2是完成15,000种化合物的试验屏幕，并验证，比较和对比从飞行员电气屏幕中发现的命中化合物与其他NA+传输相关的测定法。这项工作的整个目标是确定可能减轻增强的Na+转运的小分子，从而促进高血压，CF或两种人类疾病，这些化合物最终可能会转化为这些疾病的新疗法。公共卫生相关性：高血压是一种令人衰弱和常见的疾病，通常扎根于肾脏和血管系统。通常在肾脏中调节血浆盐和血压的细胞中蛋白质活性的上调，通常参与肾脏高血压疾病，高血压和血管疾病的慢性肾脏疾病。囊性纤维化是一种儿童和年轻人的疾病，由于其进行性和使人衰弱的肺部疾病导致死亡率。加速的盐吸收会脱水，导致粘稠的粘液积累，最终阻碍气流导致肺部下降。我们公司试图发现升高的盐运输抑制剂，这些抑制剂使多种人类疾病的进展混淆和加速。