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

• 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
• 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

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）：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，影响着全球数百万患者。囊性纤维化（CF）是一种遗传性疾病的肺和胃肠道系统，目前在儿童和年轻的成年人群体。高血压和囊性纤维化（CF）有什么共同点？中心的共同特征是增强吸收钠（Na+）的运输。在肾脏肾单位的后段中，跨肾上皮细胞的Na+转运增强驱动高血压;跨呼吸道上皮细胞的盐吸收加速导致CF中的气道表面脱水。血管生理学中的一个基本规则是，2x血浆Na+浓度等于正常血浆渗透压，并设定血浆容量和血压，高血压中升高的生理参数。氯分泌和Na+吸收的平衡设定了气道上皮细胞表面纤毛层的水合深度。最近的CF小鼠模型，其中上皮Na+通道（ENaC）被条件性上调，已被证明是模拟CF肺病的最佳小鼠模型。CF基因本身的敲除并不成功。Discovery BioMed，Inc. (DBM)开发了一种新型的电子高通量分子筛选形式，其中将通过评估肾脏集合管和CF气道极化上皮细胞模型中的Na+转运来发现Na+转运抑制剂（NTI）。Na+转运蛋白是两种疾病平台的共同分子靶标。众所周知，ENaC和其他上皮Na+渗透通道和转运蛋白在极化上皮细胞形式之外难以研究。由于这一事实，DBM开发了这种新型的电子HTS方法，用于在来自肾脏（以寻找对抗高血压的潜在治疗方法）和气道（以寻找对抗CF的潜在治疗方法）的极化上皮细胞模型上筛选分子库。DBM坚持一个核心原则，即如果在保持体内特征的疾病上皮细胞模型上进行筛选，则加速药物发现。DBM通过其新颖的电HTS生物测定法发现了命中化合物，其是肾集合管上皮细胞、CF气道上皮细胞或两者中Na+转运的抑制剂。这项1期SBIR提案的中心假设是，将发现新的NTI，其将被开发成用于高血压（作为大市场疾病）和CF（作为利基市场疾病）的可行疗法。第一阶段SBIR计划有两个里程碑。里程碑1旨在选择、完善和优化极化肾集合管和气道上皮细胞模型用于Na+转运抑制剂的电HTS。里程碑2是完成15，000种化合物的中试筛选，并将中试电子筛选中发现的命中化合物与其他Na+转运相关测定进行验证、比较和对比。这项工作的首要目标是确定可能减弱增强的Na+转运的小分子，这些转运促进高血压，CF或两种人类疾病，最终可能转化为这些疾病的新疗法的化合物。 公共卫生相关性： 高血压是一种使人衰弱的常见疾病，通常扎根于肾脏和血管系统。调节血浆盐和血压的细胞（通常在肾脏中）中蛋白质活性的上调通常涉及肾性高血压病症、慢性肾病伴高血压和血管疾病。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而导致死亡。盐的加速吸收使气道脱水，并导致粘性粘液积聚，最终阻碍气流，导致肺功能下降。我们公司寻求找到盐转运升高的抑制剂，这些抑制剂可以混淆和加速多种人类疾病的进展。