Effect of muscarinic receptor agonist on cilia sensory function and structure

毒蕈碱受体激动剂对纤毛感觉功能和结构的影响

• 批准号: 10025768
• 负责人: Wissam Aboualaiwi
• 金额: $ 3.42万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10025768
• 关键词: Acetylcholine; Affect; Agonist; Alzheimer' s Disease; Anabolism; Autosomal Dominant Polycystic Kidney; Biochemical Reaction; Biological Assay; Biology; Blood Pressure; Blood Vessels; Calcium; Calcium Signaling; Calcium oxide; Cardiovascular Diseases; Cell Line; Cell model; Cells; Chemicals; Cholinergic Receptors; Chronic Kidney Failure; Cilia; Defect; Development; Diabetes Mellitus; Disease; End stage renal failure; Endothelial Cells; Endothelium; Essential Hypertension; Exhibits; Goals; Human; Human Pathology; Hypertension; In Vitro; Individual; Laboratories; Lead; Length; Liquid substance; Mechanics; Molecular; Morbidity - disease rate; Mus; Muscarinic Acetylcholine Receptor; Muscarinics; Neurotransmitters; Nitric Oxide; Organelles; Pathway interactions; Patients; Phenotype; Physiological; Play; Polycystic Kidney Diseases; Production; Reaction; Receptor Activation; Regulation; Renal tubule structure; Research; Risk Factors; Role; Scientific Advances and Accomplishments; Sensory; Stimulus; Structure; System; Testing; Time; United States; Vascular Endothelial Cell; Vasodilation; Vasodilator Agents; cholinergic; ciliopathy; efficacy testing; interest; mortality; mutant; new therapeutic target; novel; response; shear stress

Abstract: Primary endothelial cilia are mechanosensory organelles that are projected into the lumen of blood vessels and kidney tubules. Defects in cilia assembly or function can lead to multiple human pathologies, including hypertension and Polycystic Kidney Disease (PKD). Acetylcholine, a neurotransmitter, is implicated in essential hypertension in humans. It has been demonstrated that vascular endothelia require primary cilia to sense and transmit external mechanical stimuli into internal biochemical reactions. One of these reactions includes the biosynthesis and release of nitric oxide, which is one of the most potent endogenous vasodilators. Though both primary cilia and muscarinic acetylcholine receptors play important roles in hypertension, their relationship has never been explored. To determine the roles of the cholinergic system and mechanosensory cilia, we studied the effects of acetylcholine receptor modulators on ciliary length and function in wild-type (WT) and mechano- insensitive cilia mutant endothelial cells (Pkd1−/− and Tg737orpk/orpk). Studies from our lab showed for the first time that mouse vascular endothelia exhibit muscarinic receptor-type 1, 3 and 5 (AChM1, 3, and 5R), which co- localizes to primary endothelial cilia. AChM3R activation significantly increases cilia length in cells treated with AChM3R agonist compared to non-treated cells. Furthermore, the chemosensory function of cilia can alter the mechanosensory function through changes in sensitivity to fluid-shear stress. We propose that activated ciliary AChM3R has a functional mechanosensory role in endothelial cells. This could enhance cilia sensory function in response to NO production.

摘要： 初级内皮纤毛是投射到血管腔中的机械感觉细胞器， 肾小管纤毛组装或功能的缺陷可导致多种人类病理，包括 高血压和多囊肾病（PKD）。乙酰胆碱是一种神经递质， 人类的高血压已经证明，血管内皮细胞需要初级纤毛来感觉和 将外部机械刺激转化为内部生化反应。这些反应之一包括 一氧化氮是最有效的内源性血管扩张剂之一。尽管两 原发性纤毛和毒蕈碱型乙酰胆碱受体在高血压中起重要作用，它们之间的关系已被证实。 从未被探索过。为了确定胆碱能系统和机械感觉纤毛的作用，我们研究了 乙酰胆碱受体调节剂对野生型（WT）和机械型（mechano）中纤毛长度和功能的影响。 不敏感纤毛突变内皮细胞（Pkd 1 −/−和Tg 737 orpk/orpk）。我们实验室的研究首次表明 小鼠血管内皮细胞显示毒蕈碱受体1、3和5型（AChM 1、3和5 R）， 定位于初级内皮纤毛。AChM 3R活化显著增加用以下处理的细胞中的纤毛长度： AChM 3R激动剂与未处理的细胞相比。此外，纤毛的化学感受功能可以改变细胞的化学感受功能。 通过对流体剪切应力的敏感性的变化来增强机械感觉功能。我们认为激活的纤毛 AChM 3R在内皮细胞中具有功能性机械感觉作用。这可以增强纤毛感觉功能 一是生产NO。