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

基本信息

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
项目类别：
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&apos 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

Acetylcholine Affect Agonist Alzheimer&apos 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

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项目摘要

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.

抽象的：原发性内皮纤毛是注射到血管和血管腔内的机械感觉细胞器肾小管。纤毛组装或功能的缺陷会导致多种人类病理，包括高血压和多囊性肾脏疾病（PKD）。乙酰胆碱是一种神经递质，在必需品中暗示人类的高血压。已经证明血管内皮需要原发性纤毛才能感知和将外部机械刺激传递到内部生化反应中。这些反应之一包括一氧化氮的生物合成和释放，这是最有效的内源性血管扩张剂之一。虽然两者兼而有之原发性纤毛和毒蕈碱乙酰胆碱受体在高血压中起重要作用，它们的关系具有从未探索过。为了确定胆碱能系统和机理感觉纤毛的作用，我们研究了乙酰胆碱受体调节剂对野生型（WT）和机械纤维长度和功能的影响不敏感的纤毛突变体内皮细胞（PKD1 - / - 和TG737ORPK/ORPK）。我们实验室的研究首次显示小鼠血管内皮表现出毒蕈碱受体类型1、3和5（ACHM1、3和5R），这是共同的定位于原发性内皮纤毛。 ACHM3R激活显着增加了用与未处理的细胞相比，ACHM3R激动剂。此外，纤毛的化学感应功能可以改变机械增强功能通过对流体剪切应力的敏感性改变。我们建议激活睫状 ACHM3R在内皮细胞中具有功能机理的作用。这可以增强纤毛的感觉功能响应没有生产。