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The Effect of Muscarinic Modulators on Cilia Structure and Function

Gibson, Hayley
http://rave.ohiolink.edu/etdc/view?acc_num=mco1499104909617105

Abstract Details

2017, Master of Science (MS), University of Toledo, Pharmaceutical Sciences (Pharmacology/Toxicology).
Primary endothelial cilia are microtubule-based organelles that act as mechano-sensors to help detect and respond to changes in the extracellular environment. One of these responses includes its ability to detect fluid flow and blood pressure, and translating that signal into a biochemical process to synthesize nitric oxide, an endogenous vasodilator. Abnormal cilia structure and function have been known to cause a myriad of human disorders, including polycystic kidney disease (PKD) and hypertension. It is also well documented that the acetylcholine muscarinic 1 receptor (AChM1R) plays a key role in producing a vasodilation response in the vasculature. However, much remains to be learned about the relationship between primary endothelial cilia and AChM1R. To understand more about the relationship between AChM1R and the mechano-sensory function of primary cilia, the effects of muscarinic modulators on cilia length and function in wild-type, and mechano-insensitive cilia mutant endothelial cells, Pkd1-/- (dysfunctional cilia) and Tg737orpk/orpk (cilia-less) were examined. We show that AChM1R localizes to primary endothelial cilia. AChM1R activation leads to a significant increase in cilia length in endothelial cells treated with CDD102A, an AChM1R agonist, compared to non-treated cells (1.21 ± 0.07µm vs. 2.33 ± 0.04µm for wild-type, 1.02 ± 0.01µm vs. 1.44 ± 0.01µm iv for Pkd1-/-, and 0.024 ± 0.005µm vs. 0.3 ± 0.004µm for Tg737orpk/orpk). Treating endothelial cells with pirenzepine, an AChM1R antagonist, led to a significant decrease in cilia length compared to non-treated cells (1.34 ± 0.02µm vs. 1.15 ± 0.01µm in wild-type, and 1.16 ± 0.01µm vs. 0.71 ± 0.01µm in Pkd1-/-). Treatment with CDD102A also significantly upregulated expression of AChM1R and phosphorylated eNOS. The data gathered from these experiments demonstrate an effect of AChM1R on cilia structure and function, and potentially their role in PKD and hypertension.
Wissam AbouAlaiwi (Committee Chair)
William Messer (Committee Member)
Caren Steinmiller (Committee Member)
44 p.
Pharmacology
Polycystic kidney disease; acetylcholine muscarinic 1 receptor; primary endothelial cilia; blood pressure; hypertension; cilia length; cilia function

Recommended Citations

Citations

  • Gibson, H. (2017). The Effect of Muscarinic Modulators on Cilia Structure and Function [Master's thesis, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1499104909617105

    APA Style (7th edition)

  • Gibson, Hayley. The Effect of Muscarinic Modulators on Cilia Structure and Function. 2017. University of Toledo, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1499104909617105.

    MLA Style (8th edition)

  • Gibson, Hayley. "The Effect of Muscarinic Modulators on Cilia Structure and Function." Master's thesis, University of Toledo, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=mco1499104909617105

    Chicago Manual of Style (17th edition)

mco1499104909617105
223
© 2017, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.