Wilford Zhiyu W.

Cell-based assay development for target engagement, mechanism-of-action study, lead identification, and characterization.

My project involves assay developments, target validations, and lead identifications for neurodegenerative diseases.

Drug design of Alzheimer's Disease, targeting on protein-misfolding and neuroinflammation.

Aβ triggered proteopathic and immunopathic processes are a postulated cause of Alzheimer’s disease (AD). Aβ aggregates into oligomers and fibrils, which disrupt neuronal membrane integrity and induce cellular damage. Aβ is directly neurotoxic, but may also induce neuroinflammation through activation of microglia. My project aims to identify drug candidates that may concomitantly inhibit Aβ aggregation and neuroinflammation, and further investigate their mechanism of actions. Furosemide was initially identified as a lead compound. The results demonstrate that furosemide is a probe molecule for the treatment of neuroinflammation in AD. It inhibits proinflammatory responses, enhances anti-inflammatory responses, and promotes phagocytic activity. Mechanism studies further demonstrate that furosemide suppresses upregulation of ER-stress marker genes during inflammation, suggesting an interplay between ER-stress and inflammation. To further explore the pharmacologic effects of furosemide, my study devised and synthesized a series of furosemide analogs that target both Aβ aggregation and neuroinflammation. Forty compounds were synthesized and evaluated. Compounds 3c, 3g, and 20 inhibit Aβ oligomerization; 33 and 34 inhibit Aβ fibrilization; 3g and 34 inhibit the production of TNF-α, IL-6, and nitric oxide while downregulating the expression of COX-2 and iNOS and promoting microglial phagocytosis, addressing the combined proteopathic-immunopathic pathogenesis of AD. My study further investigates the mechanism of compound 3g focusing on the downstream signaling of ER-stress, autophagy. I identify a beneficial anti-neuroinflammatory role for mild ER-stress mediated autophagy. This protective mechanism is impaired during prolonged neuroinflammation. Compound 3g is capable of restoring the protective effects of autophagy through mTOR. In addition, 3g attenuates the downregulation of ER-phagy receptor TEX264 during neuroinflammation, suggesting promoted ER self-renovation.

Working on Portable Purifier Desin, Vacuum Desiccant Cooling Garment Design

Working in CO2 storage group Responsible for sample preparation, data analysis, simulation of gas transportation and geochemical reactions, writing reports.

Research Assistant in pharmaceutical labs and fermentation labs.

Tryptophan Metabolism as a druggable target for the Proteopathy and Immunopathy of the Alzheimer's Disease

MASc student Research Area: chemical engineering, thermodynamics and geochemistry Thesis: Effects of impurities on CO2 geological storage

BASc in Pharmaceutical Science Research Assistant in microbiology lab and molecular pharmacology lab. Research Area: molecular biology, pharmacology, biochemistry, genetic engineering, protein expression. Thesis: The protein expression, purification conditions optimization and design of recombinant human bone morphogenetic protein BMP