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: 7853245
• 负责人: Erik Mills Schwiebert
• 金额: $ 1.55万
• 依托单位: DISCOVERYBIOMED, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7853245
• 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; Cystic Fibrosis; Dehydration; 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; Pulmonary Cystic Fibrosis; Research; Resistance; Screening procedure; Small Business Innovation Research Grant; Sodium; Sodium Chloride; Source; Surface; Systemic disease; Testing; Therapeutic; Time; Up-Regulation; Vascular Diseases; Vascular System; Work; absorption; abstracting; 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; meetings; monolayer; mortality; mouse model; novel; novel therapeutics; programs; public health relevance; 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.

高血压是一种混杂的多因素疾病，影响着全世界数百万患者。囊性纤维化（CF）是一种肺部和胃肠道系统的遗传性疾病，常见于儿科和青年人群。高血压和囊性纤维化有什么共同之处？中心的共同特点是增强吸收钠（Na+）运输。肾后段肾上皮细胞内Na+转运增加导致高血压；呼吸上皮细胞加速盐吸收导致CF患者气道表面脱水。血管生理学的一个基本规律是，2倍的血浆Na+浓度等于正常的血浆渗透压，并设定血浆容量和血压（高血压患者升高的生理参数）。氯化物分泌和Na+吸收的平衡决定了气道上皮细胞表面纤毛层的水化深度。最近一种上皮Na+通道（ENaC）有条件上调的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基因本身的敲除并不成功。DiscoveryBioMed, Inc. （DBM）开发了一种新的电高通量分子筛选格式，通过评估肾集管和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（NTIs）。Na+转运蛋白是这两种疾病平台的共同分子靶点。众所周知，ENaC和其他上皮Na+渗透性通道和转运体很难在极化上皮细胞外进行研究。由于这一事实，DBM开发了这种新颖的电HTS方法来筛选来自肾脏（寻找治疗高血压的潜在疗法）和气道（寻找治疗CF的潜在疗法）极化上皮细胞模型上的分子文库面板。DBM持有一个核心原则，即如果在保持体内特征的疾病上皮细胞模型上进行筛选，则药物发现将加速。DBM通过其新颖的电HTS生物测定法发现了hit化合物，这些化合物是肾集管上皮、CF气道上皮或两者中Na+运输的抑制剂。这项1期SBIR提案的中心假设是，将发现新的nti，并将其开发成可行的治疗方法，用于作为大市场疾病的高血压和作为利基市场疾病的CF。第一阶段SBIR项目有两个里程碑。里程碑1旨在选择、完善和优化极化肾收集管和气道上皮细胞模型的使用，用于Na+转运抑制剂的电HTS。里程碑2是完成15,000种化合物的先导筛选，并将从先导电筛选中发现的成功化合物与额外的Na+转运相关分析进行验证、比较和对比。这项工作的首要目标是确定可能减弱导致高血压、CF或两种人类疾病的Na+转运增强的小分子，这些化合物最终可能转化为这些疾病的新疗法。