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The Mechanisms Underlying Tissue Factor and Tenascin-C Production by Airway Epithelial Cells During Airway Constriction and SARS-CoV-2 Infection.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The Mechanisms Underlying Tissue Factor and Tenascin-C Production by Airway Epithelial Cells During Airway Constriction and SARS-CoV-2 Infection./
作者:	Mwase, Chimwemwe.
面頁冊數:	1 online resource (150 pages)
附註:	Source: Dissertations Abstracts International, Volume: 84-12, Section: B.
Contained By:	Dissertations Abstracts International84-12B.
標題:	Molecular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30491901click for full text (PQDT)
ISBN:	9798379616069

The Mechanisms Underlying Tissue Factor and Tenascin-C Production by Airway Epithelial Cells During Airway Constriction and SARS-CoV-2 Infection.
Mwase, Chimwemwe.

The Mechanisms Underlying Tissue Factor and Tenascin-C Production by Airway Epithelial Cells During Airway Constriction and SARS-CoV-2 Infection. - 1 online resource (150 pages)

Source: Dissertations Abstracts International, Volume: 84-12, Section: B.

Thesis (Ph.D.)--Harvard University, 2023.

Includes bibliographical references

During asthma exacerbations, the airway constricts and exposes the airway epithelium to mechanical compression. Using an in vitro model mimicking the mechanical compression imposed on airway epithelial cells during an asthma exacerbation, we have shown that mechanical compression of well-differentiated human bronchial epithelial (HBE) cells recapitulates the structural changes that occur in the airway in asthma, which are described in Chapter 1. To add to the structural changes, compressed HBE cells are also a source of mediators that have been implicated in asthma. In this dissertation, I focused on two proteins, namely tissue factor (TF) and tenascin-C (TNC).TF initiates the extrinsic coagulation pathway. In fact, in asthma, the increased levels of TF and other procoagulant mediators contribute to the well-known procoagulant environment in the airway in patients with asthma. TF expression is increased in the airway epithelium of patients with asthma, yet the role of increased TF in asthma is unknown. In well-differentiated primary HBE cells, mechanical compression increases TF production and the release of extracellular vesicles (EVs), which are membrane-bound vesicles that are released from cells. In Chapter 2, I describe our work investigating the role of house dust mite (HDM), an allergen associated with asthma pathogenesis, in modulating TF production in vivo in mice and in vitro in airway epithelial cells. In mice, TF production was increased only in female mice, while in HBE cells, HDM did not robustly increase mRNA and had no effect on protein release, even when combined with mechanical compression. We additionally showed that the mechanical compression-induced production of TF in HBE cells depends on the transforming growth factor-β1 (TGF-β) receptor signaling pathway. Finally, I describe our proteomic analysis to identify novel proteins contained in EVs that are released from compressed HBE cells.In Chapter 3, I describe the production of an extracellular matrix protein, TNC, in response to airway constriction. In patients with asthma, TNC is abundantly expressed in the subepithelial basement membrane which is located below the airway epithelium. We observed that in response to mechanical compression, TNC production is induced, regardless of the disease status of the HBE cells. We further showed that in compressed HBE cells, there is polarized release of TNC to the apical and basolateral sides on the epithelial cells, although the basolateral secretion is preferred. The compression- induced production of TNC from HBE cells depends on extracellular signal-regulated kinases (ERK) or the TGF-β receptor signaling pathways. Finally, we discovered that in compressed HBE cells, TNC is released through both non-EV and EV mechanisms.With the onset of the coronavirus disease 19 (COVID-19) pandemic, we decided to apply our expertise in airway epithelial biology to better understand why the elderly are more susceptible to severe COVID-19 outcomes. In Chapter 4, I describe our work investigating the replication kinetics of SARS-CoV-2 variants including the ancestral Washington, Delta, and Omicron (BA.1) in HBE cells from young and elderly donors. In our infection model, we did not observe any age specific differences in viral replication, but the rate of replication of Delta was greater. We additionally examined the production of TF and TNC in response to infection with SARS-CoV-2. In patients with COVID-19, both TF and TNC have been shown to be elevated in bronchoalveolar lavage fluid (BALF) and serum. While SARS-CoV-2 infection has no effect on TF production, only Delta and Omicron variants elicited basolateral release of TNC, but not apical release.Overall, the chapters investigate how TF and TNC production are regulated by airway constriction and SARS-CoV-2 infection.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798379616069Subjects--Topical Terms:

517296
Molecular biology.
Subjects--Index Terms:

Airway epithelial cellsIndex Terms--Genre/Form:

542853
Electronic books.

The Mechanisms Underlying Tissue Factor and Tenascin-C Production by Airway Epithelial Cells During Airway Constriction and SARS-CoV-2 Infection.
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