Non-motile primary cilia are organelles found on the surface of most cells where they play pivotal sensory and signaling roles required for normal human development and organ function. Defects in cilia assembly or function can lead to multiple human pathologies, collectively known as ciliopathies, including polycystic kidney disease and several other syndromes. Primary endothelial cilia are mechanosensory organelles that are projected into the lumen of blood vessels. 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. This idea has only been investigated in cultured endothelial cells in vitro. Based on this finding, a very bold hypothesis is formed to test that abnormal cilia function results in vascular hypertension. New and surprising data that were recently generated by the PI show that muscarinic acetylcholine receptors, which has been known to regulate blood pressure, are localized to primary cilia and can modulate cilia length and function. This project will, therefore, utilize state-of-the-art approaches to test these highly innovative concepts. A series of conditional mouse models will be used, coupled with high-resolution microscopy techniques. In Aim 1, we will use vascular-specific mouse models of Tg737 and AChM3R to study systolic/diastolic blood pressure and characterize vascular function. In Aim 2, the expression and localization of muscarinic receptors will be investigated in primary cilia dysfunction (PKD). Moreover, the function of ciliary AChM3R will be analyzed in vitro using well-characterized wild-type and cilia mutant endothelial cell lines. We will study the mechanism of Cilia-AChM3R, including blood pressure control in matured adult vascular system. Most importantly, we will test a pharmacological intervention to reduce blood pressure in our animal models by bypassing cilia function. Overall, the proposed studies will fill a critical gap in our existing knowledge by providing novel information on the physiology of cilia and ciliary AChM3R and will advance the larger field of primary cilia signaling particularly in relation to blood pressure control function.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2019 → 12/31/2020|