Validation and Mechanism Studies of Novel Therapeutic Compounds Modulating Angiogenesis

• Main Author: Tat, Jennifer
• Other Authors: Wen, Xiao-Yan
• Language: en_ca
• Published: 2013
• Subjects: angiogenesis; zebrafish; drug discovery; fenretinide; indirubin-3-monoxime; dihydromunduletone; 0719
• Online Access: http://hdl.handle.net/1807/35693

Discovering novel compounds that stimulate or abrogate angiogenesis can lead to development of new therapeutic agents that may effectively treat diseases with pathological angiogenesis. The zebrafish model allows for a whole-organism approach to drug discovery. Advantages over other animal models include small embryo size, fecundity, rapid embryonic development, optical clarity and easy accessibility of the embryos. My goal is to validate the therapeutic efficacy and identify the molecular mechanisms of action of three compounds identified from our previous chemical genetic screens. Fenretinide promoted angiogenesis in zebrafish embryos but inhibited the angiogenesis-dependent process of fin regeneration. The pro-angiogenic effects of fenretinide appear secondary to the stimulation of somitogenesis. I3M potently inhibited angiogenesis and fin regeneration, and may act partially through the notch pathway. Lastly, I validated the anti-angiogenic effect of a novel compound DHM. Comprehensively, my studies support the utility of zebrafish as a versatile tool for anti-angiogenic drug discovery.