Term of Award
Fall 2021
Degree Name
Master of Science in Biology (M.S.)
Document Type and Release Option
Thesis (restricted to Georgia Southern)
Copyright Statement / License for Reuse
Digital Commons@Georgia Southern License
Department
Department of Biology
Committee Chair
Vinoth Sittaramane
Committee Member 1
Shainaz Landge
Committee Member 2
Scott Harrison
Abstract
The zebrafish (Danio rerio) melanocyte system offers an informative and translational, high-throughput (HTP) model for preclinical drug discovery. High fecundity, rapid development and ex-vivo fertilization allow for rapid drug screens to be employed with large sample sizes. Similar neuro-development pathways and a high degree of homology to humans has established zebrafish as a keystone model of neurological disorders. Specifically, melanocyte physiology and melanogenesis have been tied to intracellular signal transduction pathways and catecholamine biosynthesis. As a result, phenotypic screens of melanocytes have proven useful for indicating physiological changes on a molecular level. The prevalence of zebrafish as a model in literature has generated a vast catalogue of comparable phenotype characterizations, making it an optimal candidate for HTP studies. In this study, two groups of novel small molecules were synthesized using green chemistry practices (3,4,6-trisubstituted pyridazines and ortho-substituted bisfunctionalized triazoles). Both groups have exhibited anticancer, antiviral and antidepressant properties, amongst others. Pyridazines and triazoles were assessed for their clinical potential by screening for toxicity and biological activity in zebrafish. It was found that pyridazines induce melanosome aggregation and analgesia in treated zebrafish - indicative of agonistic interaction with the alpha-2a adrenoceptor. Zebrafish treated with triazoles exhibited a depigmentation phenotype. Depigmentation was hypothesized to result from triazole induced tyrosinase inhibition, which was subsequently assessed via a biochemical inhibition assay – which exhibited a significant reduction in tyrosinase activity. Although both compound classes induced physiological changes, studies must be progressed to mammalian models to further characterize clinical potential and exact mechanisms of action.
Recommended Citation
Philp J. (2021). Identification and characterization of clinically relevant small molecules using Zebrafish (Danio rerio) melanocyte systems (unpublished master's thesis). Georgia Southern University, USA.
Research Data and Supplementary Material
No
