Are you looking for a Master's project and think it could be exciting to get into the private industry and get working experience inside a company, then this project might be for you.
Title: Exploring Novel Collagen NC-1 domain Derived Peptides as Potential Anti-angiogenic Therapy in Cancer
Imbalances in angiogenesis occur in a range of different pathologies, especially cancer and fibrosis. 1,2,3,4 The extracellular matrix (ECM) is a major player and a critical component in the regulation of Angiogenesis. Collagens are part of the ECM, but not just for structural framework some also contain key signaling properties, such as those containing NC-1 domains.5,6,7
Endostatin is an example of an NC-1 domain, inhibiting angiogenesis, and thereby showing promise as a therapy for diseases characterized by aberrant angiogenesis.8 This make makes endostatin an attractive drug target as it is more versatile compared to for instance the current class of anti-angiogenesis antibodies aiming for loss-of-function by targeting the VEGFR-2/KDR. However, despite the circumstantial testing utilizing endostatin as a therapy has not yet been successful to a large extent, and thus there is a need for a better understanding of how the potential of endostatin can be realized. 8,9,10
Furthermore, collagen signaling is still in its infancy, and the function of many of the NC-1 domains of the lesser known collagens are simply not known, or even named, and we hypothesize collagens related to type XVIII, e.g. type XV, but also other collagens, such as the much less explored type IV and XIX, propose an interesting target in terms of novel treatment modalities for controlling tissue remodeling and tissue remodeling in cancer and possibly fibrosis, namely angiogenesis.
Aims and approach:
This project will focus on Exploring Novel Collagen NC-1 domain Derived Peptides as Potential Anti-angiogenic Therapy in Cancer.
1) Build assays allowing determination of the activity of the potential anti-angiogenic peptides
2) Identifying novel NC-1 based fragments with anti-angiogenic properties
3) Determine how significant the inter-collagen difference is in anti-angiogenic potency between NC-1 domains.
4) To characterize an in vivo mice model to investigate the effect of anti-angiogenetic NC1 domain peptides on bone growth. The emphasis will be on histological assessment of bone measuring the size of the chondrocyte zone.
In vitro: Optimization of primary HUVEC cells, using different cellular assays to understand the mode of actions of designed NC1 domain collagen fragments in relation to ERK, tube formation and migration.
In vivo: Histological and immunohistochemical examination of bone will be used to assess treatment effect on the size of the chondrocyte zone as chondrocytes are important for heathy bone structure using hematoxylin and eosin (H&E) staining.
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- Walia, A. et al. Endostatin’s emerging roles in angiogenesis, lymphangiogenesis, disease, and clinical applications. Biochim. Biophys. Acta 1850, 2422–38 (2015).
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- Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–74 (2011).
- Lafoz, E., Ruart, M., Anton, A., Oncins, A. & Hernández-Gea, V. The Endothelium as a Driver of Liver Fibrosis and Regeneration. Cells 9, 1–26 (2020).
- Karsdal, M. A. et al. The good and the bad collagens of fibrosis – Their role in signaling and organ function. Adv. Drug Deliv. Rev. 121, 43–56 (2017).
- Karsdal, M. A. Biochemistry of Collagens, Laminins and Elastin. Book vol. 1st Editio (Elvsevier, 2016).
- Karsdal, M. A. et al. Is the Total Amount as Important as Localization and Type of Collagen in Liver Fibrosis Attributable to Steatohepatitis? Hepatology 71, 346–351 (2020).
- O’Reilly, M. S. et al. Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth. Cell 88, 277–285 (1997).
- Morbidelli, L., Donnini, S., Chillemi, F., Giachetti, A. & Ziche, M. Angiosuppressive and Angiostimulatory Effects Exerted by Synthetic Partial Sequences of Endostatin. Clin. Cancer Res. 9, 5358–5369 (2003).
- Folkman, J. Antiangiogenesis in cancer therapy - Endostatin and its mechanisms of action. Exp. Cell Res. 312, 594–607 (2006).