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Role of muscarinic receptor anatgonist in primary cilia structure

毒蕈碱受体拮抗剂在初级纤毛结构中的作用

基本信息

批准号：
10055100
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：
2020-05-01 至 2021-12-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10055100
关键词：
Acetylcholine Agonist Alzheimer&apos s Disease Anabolism Biochemical Reaction Biology Blood Vessels Cardiovascular Diseases Cell Line Cells Cholinergic Receptors Cilia Defect Development Diabetes Mellitus Disease End stage renal failure Endothelial Cells Endothelium Essential Hypertension Exhibits Functional disorder Future Goals Human Human Pathology Hypertension Kidney Lead Length Liquid substance Measures Mechanics Molecular Mus Muscarinic Acetylcholine Receptor Muscarinics Neurotransmitters Nitric Oxide Organelles Pathology Patients Phenotype Physiological Play Polycystic Kidney Diseases Production Reaction Regulation Renal function Renal tubule structure Research Risk Factors Role Sensory Stimulus Structure System Testing Time United States Vasodilation Vasodilator Agents cholinergic ciliopathy in vitro testing interest mutant novel response shear stress therapeutic target

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. We propose in the current study that AChM3R antagonist will have the opposite effect and shorten cilia length. This could also diminish cilia sensory function in response to NO production.

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