Sodium Transport Inhibitors for Hypertension and Cystic Fibrosis

描述(申请人提供)：治疗高血压和囊性纤维化的钠转运抑制剂科学摘要描述高血压是一种令人困惑的多因素疾病，影响全球数百万患者。囊性纤维化是一种遗传性肺部和胃肠系统疾病，见于儿科和青壮年人群。高血压和囊性纤维化有什么共同之处？主要的共同特征是增强了钠离子的吸收转运。肾单位后段肾上皮细胞Na+转运增加导致高血压；呼吸上皮细胞加速盐分吸收导致慢性阻塞性肺疾病的呼吸道表面脱水。血管生理学中的一个基本规则是，2倍的血浆Na+浓度等于正常血浆渗透压，并决定血浆容量和血压，这是高血压患者升高的生理参数。氯离子分泌和Na+吸收的平衡决定了呼吸道上皮细胞表面纤毛层的水化深度。最近的一种上皮性钠离子通道(ENaC)条件性上调的CF小鼠模型已被证明是模拟CF肺部疾病的最佳小鼠模型。Cf基因本身的敲除就没有那么成功了。DiscoveryBioMed，Inc.(DBM)开发了一种新颖的电子高通量分子筛选格式，其中将通过评估Na+通过肾脏集合管和CF呼吸道的极化上皮细胞模型的Na+运输来发现Na+运输抑制物(NTIS)。Na+转运蛋白是两种疾病平台的共同分子靶点。众所周知，ENAC和其他上皮Na+通透通道和转运体很难在极化的上皮细胞形式之外进行研究。由于这一事实，DBM开发了这种新颖的电子HTS方法，以筛选来自肾脏(寻找潜在的治疗高血压的药物)和呼吸道(寻找治疗CF的潜在药物)极化上皮细胞模型上的分子库的面板。DBM坚持一个核心原则，即如果对保持体内特征的疾病的上皮细胞模型进行筛查，药物发现就会加快。DBM通过其新颖的电子HTS生物测定发现了命中的化合物，这些化合物是肾脏集合管上皮细胞和/或CF呼吸道上皮细胞中Na+运输的抑制剂。这一第一阶段SBIR提案的中心假设是，将发现新的NTIS将被开发成作为一种大市场疾病的高血压和作为一种利基市场疾病的CF的可行疗法。该第一阶段SBIR计划有两个里程碑。里程碑1旨在选择、完善和优化极化肾脏集合管和呼吸道上皮细胞模型用于Na+转运抑制剂的电子HTS。里程碑2是完成15,000种化合物的中试筛选，并用额外的与Na+转运相关的分析来验证、比较和对比从试点电子筛查中发现的命中化合物。这项工作的总体目标是识别可能减弱导致高血压、CF或这两种人类疾病的Na+转运增强的小分子，这些化合物最终可能转化为治疗这些疾病的新疗法。 公共卫生相关性： 高血压是一种使人衰弱的常见疾病，通常植根于肾脏和血管系统。调节血浆盐和血压的细胞中蛋白质活性上调，通常在肾脏，通常与肾性高血压疾病、慢性肾脏疾病伴高血压和血管疾病有关。囊性纤维化是一种儿童和年轻人的疾病，由于其进行性和衰弱的肺部疾病而导致死亡。盐的加速吸收会使呼吸道脱水，并导致粘性粘液堆积，最终阻碍气流，导致肺功能下降。我们公司寻求寻找抑制盐分运输升高的药物，以迷惑和加速多种人类疾病的进展。

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.