Elucidating the role of the TGF-β superfamily signaling in pulmonary vascular cell proliferation
Pulmonary arterial hypertension is a fatal disease characterized by the remodeling of the pulmonary vasculature. Aberrant proliferation of pulmonary arterial endothelial cells and smooth muscle cells is the primary factor contributing to vascular obstruction and the development of plexiform lesions. It is known that germline mutations in BMPR2 (~70%), ALK1, BMP9, and BMP10 are associated with both familial PAH and idiopathic PAH, indicating that TGF-β signaling plays a significant role in PAH. Even in the absence of BMPR2 mutations, there is a decrease in BMPR2 signaling and an increase in TGF-β signaling. Therefore, the imbalance of BMPR2/TGF-β signaling may contribute to the pathogenesis of PAH. However, the molecular mechanisms behind the imbalance of BMPR2/TGF-β signaling that result in the proliferation of pulmonary vasculature cells are still not fully understood. The fact that TGF-growth factors can interact with multiple TGF-type II receptors or that different growth factors can bind to the same receptors makes TGF signaling more complex. In this dissertation, I concentrate on TGF-β signaling focusing on two major aspects. One of my hypothesis is that mutations in the BMPR2 gene may alter their binding affinity to growth factors, changing their preference for binding and possibly triggering a signaling switch. The pro-proliferative status in pulmonary artery endothelial cells and pulmonary arterial smooth muscle cells could arise from these changes in PAH. In this dissertation, I aim to explore the interactions between the TGF-β growth factors and the TGF-β Type II receptor BMPR2, as well as compare the growth factor binding sites of Type II receptors. Furthermore, I intend to examine the impact of BMPR2 mutations identified in PAH patients on receptor binding interactions and elucidate the role of TGF-β signaling in pulmonary arterial endothelial cell proliferation. This will enhance our understanding of the mechanistic role of TGF-β signaling in PAH.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
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Theses
- Authors
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Chu, Kit Yee
- Thesis Advisors
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Martinez-Hackert, Erik
- Committee Members
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LaPres, John
Ralston, Amy
Henry, Bill
Schutte, Brian
- Date
- 2023
- Subjects
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Biochemistry
- Program of Study
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Biochemistry and Molecular Biology - Doctor of Philosophy
- Degree Level
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Doctoral
- Language
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English
- Pages
- 116 pages
- Permalink
- https://doi.org/doi:10.25335/59ts-np88