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dc.contributor.advisorMorgan, Kathleen G.en_US
dc.contributor.authorXing, Yien_US
dc.date.accessioned2019-08-05T14:38:57Z
dc.date.issued2019
dc.identifier.urihttps://hdl.handle.net/2144/37004
dc.description.abstractThis project focused on extracellular signal-regulated kinase (ERK) and focal adhesion proteins related to ERK activity, and found a novel signaling pathway contributing to aging-related defects in smooth muscle contractility. Previous members of our lab have used ERK inhibitors to demonstrate the role of ERK in smooth muscle contraction. Dr. Nicholson used the ERK inhibitor FR 18024 and noted that, in the presence of this inhibitor phenylephrine (PE) induced a higher stress increase in young mouse aortas compared to old aortas. Inhibition of the kinase ERK abolished this difference. He also quantitated ERK phosphorylation, a marker of ERK activation in PE-stimulated aortas from both young and aged mice and found a significant lower level of phosphorylated-ERK (p-ERK) in aged mouse aortas. I was interested in determining the substrate of ERK that is affected in aging. Caldesmon (CaD) is one of the known substrates of ERK in smooth muscle. More importantly, CaD, as an actin-binding protein, inhibits cross-bridge formation by blocking the interaction between actin and myosin. Thus, I tested the hypothesis that, caldesmon phosphorylation is inhibited in aged mouse aortas. To determine the mechanism by which regulation of ERK activation changes with age, the role of micro-RNAs (miRs) in the regulation ERK phosphorylation was investigated. Transfection of miR-137 and -34a into A7r5 cells resulted in a significantly lower level of p-ERK in response to the phorbol ester DPBA. Further, together with my collaborators I found that transfection of miR-137 and -34a led to significantly decreased focal adhesion protein levels in A7r5 smooth muscle cells, such as paxillin and src. To confirm whether focal adhesion proteins contribute to the impairment of agonist-induced ERK phosphorylation, paxillin siRNA and src inhibitor were used. The results showed that paxillin is required for the phosphorylation of ERK1 and ERK2 and src is required for ERK2 phosphorylation. In conclusion, age-related increases in miR-137 and -34a decrease ERK phosphorylation via downregulation of paxillin and src. The decrease in ERK phosphorylation leads to a decrease in CaD phosphorylation and inhibits contraction. Thus, the thin filament-coupled pathway in differentiated vascular smooth muscle is inhibited in the aged mouse aorta and this leads to aging-associated defects in smooth muscle contractility.en_US
dc.language.isoen_US
dc.subjectPhysiologyen_US
dc.subjectActinen_US
dc.subjectMouse aortaen_US
dc.subjectThin filamenten_US
dc.titleAn ERK-dependent signaling pathway regulated by miRs contributes to an aging-related decrease in smooth muscle contractility by inhibiting caldesmon phosphorylationen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2019-06-19T01:02:57Z
dc.description.embargo2021-06-18T00:00:00Z
etd.degree.nameMaster of Scienceen_US
etd.degree.levelmastersen_US
etd.degree.disciplineSargent College of Health and Rehabilitation Sciencesen_US
etd.degree.grantorBoston Universityen_US


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