Modulating the activation and inhibition of the met-hepatocyte growth factor (HGF) signaling axis using engineered proteins
Abstract/Contents
- Abstract
- Complex cell signaling pathways are ubiquitous and essential in nature. Extracellular signaling events often rely on interaction of a growth factor ligand with its cognate receptor, which in turn stimulates a cellular response. The themes of this dissertation are centered on a signaling axis comprised of the hepatocyte growth factor (HGF) ligand and the receptor tyrosine kinase, Met. Activation of this biochemical pathway is associated with wound healing and embryonic development. Conversely, dysregulation of Met-HGF signaling can lead to uncontrolled tumor growth and eventual metastasis of many common human cancers. Thus, there has been great interest in the development of therapeutic agents that can either stimulate or inhibit Met activation for tissue regeneration or cancer therapy, respectively. An alternative component of the Met-HGF signaling axis is a protease, known as matriptase, capable of cleaving inactive pro-HGF into active HGF. Matriptase has been shown to significantly contribute to human disease progression through dysregulated activity. In this thesis, rational and combinatorial protein engineering techniques were applied to develop novel therapeutics and molecular tools capable of restoring control and furthering the understanding of the Met-HGF signaling system. First, through blockade of matriptase activity with a high affinity engineered protein, reduced pro-HGF activation and subsequent inhibition of cancer cell invasion were demonstrated. Additionally, a novel biosensor was developed that enables characterization of matriptase activity and inhibition to provide a new approach to understanding matriptase activity and inhibitor engineering. Next, to stimulate HGF-mediated Met activation, biomaterials based approaches were used to deliver an engineered HGF mimic post myocardial infarction to provide greater regenerative outcomes in preclinical disease models. This dissertation will describe the protein engineering techniques and outcomes of each of these novel approaches for characterizing and modulating the activity of the Met-HGF signaling axis.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2017 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Mitchell, Aaron Comstock |
|---|---|
| Associated with | Stanford University, Department of Bioengineering. |
| Primary advisor | Cochran, Jennifer R |
| Thesis advisor | Cochran, Jennifer R |
| Thesis advisor | Graves, Edward (Edward Elliot), 1974- |
| Thesis advisor | Swartz, James R |
| Advisor | Graves, Edward (Edward Elliot), 1974- |
| Advisor | Swartz, James R |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Aaron Comstock Mitchell. |
|---|---|
| Note | Submitted to the Department of Bioengineering. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2017. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2017 by Aaron Comstock Mitchell
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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