A Ginsenoside TMEM16A Potentiator for Cystic Fibrosis

人参皂苷 TMEM16A 治疗囊性纤维化的增效剂

基本信息

批准号：
10574384
负责人：
Bradford Alan Woodworth
金额：
$ 22.28万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-26 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10574384
关键词：
ATP Receptors Adverse effects Agonist Airway Disease Anions Asthma Biological Assay Blood specimen Cells Chemosensitization Chronic Sinusitis Clinical Clinical Trials Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator DNA Sequence Alteration Data Disease Dose Drug Kinetics Embryo Ensure Epithelium Exhibits Functional disorder Genetic Ginseng Preparation Ginsenosides Goblet Cells Height Histologic Histopathology Hour Human Hydration status In Vitro Infection Inflammatory Ingestion Investigation Knowledge Koreans Liquid Chromatography Lung Measures Mediating Mucociliary Clearance Mucous body substance Mus Nasal Epithelium Nose Optical Coherence Tomography Oral P2Y2 receptor Panax ginseng Pathologic Pathology Pathway interactions Patients Pharmacodynamics Placebos Plasma Property Pseudomonas Randomized Rattus Role Saline Saponins Second Messenger Systems Shapes Signal Transduction Solid Sprague-Dawley Rats Testing Therapeutic Uridine Viscosity aqueous chronic pancreatitis cystic fibrosis airway cystic fibrosis patients cytokine density desensitization design effective therapy efficacious treatment efficacy evaluation experimental study human model improved in vivo indexing kidney cell mucus clearance mucus hypersecretion novel strategies patch clamp preclinical study pulmonary function response tandem mass spectrometry targeted treatment translation to humans tripolyphosphate

项目摘要

PROJECT SUMMARY Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel impedes mucus clearance and leads to the airway disease, cystic fibrosis (CF). New CFTR modulators improve mucociliary transport (MCT) and pathophysiologic manifestations of the disease in genetic mutation-specific patients, but do not completely restore airway function. We recently discovered ginsenosides derived from Korean Red Ginseng serve as potentiators of the Ca2+-activated Cl− channel (CaCC) [TMEM16A] and can restore MCT in vitro and in vivo through this alternative Cl- pathway. Yet, poor clinical trial results with activators of TMEM16A and a recently described role for the channel in mucus hypersecretion in infected airways has led to some to suggest that inhibiting TMEM16A is a better strategy. However, we hypothesize that potentiating TMEM16A, rather than channel activation through purinergic, intracellular Ca2+- driven pathways, will rescue MCT in infected CF airways. Specific Aim 1 will isolate the ginsenoside that most effectively potentiates TMEM16A and measure its effects on MCT parameters and mucus pathology. We anticipate finding the optimal ginsenoside through Ussing chamber and patch clamp experiments, while also measuring the impact on markers of MCT and mucus viscosity. Specific Aim 2 will assess whether a TMEM16A potentiator improves epithelial Cl- secretion, histopathology, and MCT parameters in infected CF rat airways. We will determine single dose pharmacokinetics for the selected ginsenoside and administer to Pseudomonas-infected CF rats to evaluate nasal potential difference, MCT, lung micro-CTs, histopathology, mucus properties (viscosity, solids, mass, density), and inflammatory cytokines. We will answer questions about the therapeutic utility of targeting the TMEM16A pathway and identify a new TMEM16A potentiator as an effective treatment for CF airway disease.

项目概要囊性纤维化跨膜电导调节器 (CFTR) Cl 通道功能障碍阻碍粘液清除并导致气道疾病、囊性纤维化 (CF) 新型 CFTR 调节剂可改善粘液纤毛。基因突变特异性患者中疾病的转运（MCT）和病理生理学表现，但是我们最近发现了源自韩国红的人参皂苷。人参作为 Ca2+ 激活的 Cl− 通道 (CaCC) [TMEM16A] 的增强剂，可以恢复 MCT 然而，TMEM16A 激活剂的临床试验结果不佳。最近描述的通道在受感染气道粘液过度分泌中的作用导致了一些建议抑制 TMEM16A 是更好的策略，然而，我们发现了增强 TMEM16A 的能力。而不是通过嘌呤能、细胞内 Ca2+ 驱动的途径激活通道，将拯救 MCT 具体目标 1 将分离出最有效增强 TMEM16A 和 TMEM16A 的人参皂苷。测量其对 MCT 参数和粘液病理学的影响，我们期望找到最佳的人参皂苷。通过使用腔室和膜片钳实验，同时还测量对 MCT 标志物的影响具体目标 2 将评估 TMEM16A 增效剂是否改善上皮 Cl-。我们将确定感染 CF 大鼠气道的分泌、组织病理学和 MCT 参数。选定人参皂苷的药代动力学，并给予假单胞菌感染的 CF 大鼠进行评估鼻电位差、MCT、肺显微 CT、组织病理学、粘液特性（粘度、固体、质量、密度）和炎症细胞因子，我们将回答有关靶向治疗效用的问题。 TMEM16A 通路并确定一种新的 TMEM16A 增效剂作为 CF 气道疾病的有效治疗方法。