Gau, David
(2018)
Novel Approaches to Modulate Endothelial Cell Migration and Angiogenesis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
Angiogenesis, the process of neovascularization from pre-existing vasculature, is fundamental to development and tissue repair. However, aberrant angiogenesis exacerbates progression of a number of diseases including but not limited to cancer and diabetic retinopathy. Endothelial cell (EC) migration, a key event for angiogenesis, is a highly regulated process that critically relies on the dynamic remodeling of the actin cytoskeleton via orchestrated actions of various actin-binding proteins. An important aspect of the dynamic remodeling of the actin cytoskeleton, cell migration, and angiogenesis is stimulus-induced regulation of de novo synthesis of many important molecular components of the actin cytoskeleton by MKL (Megakaryoblastic Leukemia)–SRF (Serum-Response Factor) transcriptional machineries. Given the previous genetic evidence for the importance of MKL/SRF signaling in EC migration and angiogenesis, we first set out to explore whether angiogenesis is susceptible to small molecule-mediated inhibition of the MKL/SRF pathway. Our studies showed that CCG-1423, a small molecule inhibitor of MKL, causes a prominent defect in EC migration and angiogenesis in vitro, ex vivo, and in vivo. Inhibition of MKL led to prominent depletion of actin-binding protein Profilin-1 (Pfn1), an important molecular player of membrane protrusion and EC migration/angiogenesis, but through an unconventional indirect mechanism that involves a cellular externalization control [Angiogenesis (2017) 20(4):663-672; J. Biol Chem. (2017) 292(28):11777-11791]. Next, guided by computational-based rational design, we identified the first-generation small molecule inhibitors of the Pfn1:actin interaction, and further demonstrated the ability of these small molecules to inhibit EC migration, proliferation, and angiogenesis in vitro and ex vivo [J Biol Chem (2017) Dec 27, epub]. Finally, to gain new insights on the regulation of Pfn1, we identified and explored the consequence of novel phosphorylation event which caused insoluble aggregation of Pfn1 and actin molecules [PLoS One (2016) 26;11(5):e0156313].
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
11 June 2018 |
| Date Type: |
Publication |
| Defense Date: |
28 February 2018 |
| Approval Date: |
11 June 2018 |
| Submission Date: |
27 March 2018 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
176 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
MKL, profilin, CCG-1423, angiogenesis, cell migration |
| Date Deposited: |
11 Jun 2018 19:54 |
| Last Modified: |
11 Jun 2019 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/33991 |
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Novel Approaches to Modulate Endothelial Cell Migration and Angiogenesis. (deposited 11 Jun 2018 19:54)
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