Home
Resource
Metabolic regulation of excitation - contraction coupling in human airway smooth muscle cells
PDF
PDF format is widely accepted and good for printing.
Plug-in required
PDF-1(3.75 MB)
Citation & Export
View Usage Statistics
Staff View

Citation & Export
Hide

Simple citation

Xu, Shengjie. Metabolic regulation of excitation - contraction coupling in human airway smooth muscle cells. Retrieved from https://doi.org/doi:10.7282/t3-zekr-mm40

Export

Click here for information about Citation Management Tools at Rutgers.

Statistics
Hide

Description

TitleMetabolic regulation of excitation - contraction coupling in human airway smooth muscle cells
NameXu, Shengjie (author); Panettieri, Reynold (chair); Jude, Joseph JAJ (member); Gow, Andrew AG (member); Laskin, Debra DL (member); Bergeron, Renée RB (member); Rutgers University; School of Graduate Studies
Date Created2022
Other Date2022-05 (degree)
SubjectToxicology, Pharmacology, Molecular biology, Airway smooth muscle, Asthma, Free fatty acid receptors, Glycolysis, Metabolism, Metabolomics
Extent194 pages : illustrations
DescriptionAsthma is a chronic airway disease with a complex etiology, characterized by repeated exacerbations, bronchial spasm, and airway remodeling. Airway hyperresponsiveness (AHR) is the salient clinical feature of asthma, which consists of elevated maximal responses and sensitivity to contractile agonists. Human airway smooth muscle (HASM) cells play a pivotal role in mediating AHR. In HASM cells, interactions of contractile agonists with their membrane receptors elicit intracellular signaling events that culminate in cell shortening. These signaling cascades, collectively called excitation-contraction (EC) coupling, are amplified in asthma to mediate AHR in asthma. Numerous studies have demonstrated that metabolic dysfunctions are associated with the development of asthma and AHR. The purpose of this dissertation was to investigate the mechanistic link between cellular metabolism and airway hyperresponsiveness, through a step-by-step dissection of cellular signaling pathways in HASM cells. Obesity, a hallmark of metabolic syndrome, demonstrates distinct metabolic profiles in various cell types, including altered lipid metabolism, glucose metabolism, and energy biosynthesis. Additionally, obesity aggravates asthma by enhancing AHR and attenuating response to treatment. However, the precise mechanisms linking obesity and asthma remain unknown. The findings of this dissertation demonstrate that obesity induces a distinct metabolic profile of HASM cells, characterized by changes in glycolysis and citric acid cycle in untargeted metabolomics screening. Obese donor-derived HASM cells also showed elevated glycolysis rates, glycolytic capacity, and glycolytic enzyme expression. Therefore, we sought to examine the effect of glycolysis on AHR in human small airways. The inhibition of glycolysis attenuates agonist-induced EC coupling in HASM cells and bronchoconstriction in human precision-cut lung slices (hPCLS). Subsequent mechanistic studies demonstrated that decreased cellular ATP and phosphorylation of various proteins in the EC coupling pathway appeared to drive this bronchoprotective effect of glycolysis inhibition. In addition, the effect of another essential component of cellular metabolism, free fatty acids, on EC coupling was investigated in HASM cells. Activation of free fatty acid receptor 1 (FFAR1) attenuated agonist-induced myosin light chain (MLC) phosphorylation and cell stiffness in HASM cells. Taken together, this dissertation research provides novel insights into the metabolic regulation of AHR in airway smooth muscle and helps to potentially identify new therapeutic targets for asthma.
NotePh.D.
NoteIncludes bibliographical references
Genretheses
Persistent URLhttps://doi.org/doi:10.7282/t3-zekr-mm40
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
Version 8.5.5
Rutgers University Libraries - Copyright ©2024