Zhou Zhidong, MD, Ph.DClinician Scientist, Translational Therapeutics LaboratoryAssistant Professor, NBD, Duke-NUS Medical School
Contact Information
Translational Therapeutics LaboratoryDuke-NUS Graduate Medical School, NBD, Level 68 College Road, Singapore 169857Tel: (65) 6601 3742 (Office) Fex: (65) 6256 9178Email: [email protected]; [email protected]
Overview
Our translational studies focus on new therapeutic targets, biomarkers and neuroprotective pre-drugs for Parkinson's Disease and other neuron degenerative diseases. To achieve it, high throughput screening investigations combined with multi-disciplinary techniques, including gene-editing techniques, stem cell techniques, single cell sequencing and meta-analysis, are being performed in the lab.
First, the in vitro high throughput proteomics screening plus immuno-precipitation protocols as well as cellular and molecular techniques are utilised to search and identify key therapeutic targets, biomarkers or signaling pathways relevant to human neurodegeneration.
Second, in vitro high throughput chemical library screening is being performed to identify neuroprotective compounds or pre-drugs targeting at key molecules or signaling pathways for Hit & Lead (H & L) drug developments.
Third, key therapeutic targets, biomarkers and promising pre-drugs identified from in vitro studies are being verified, validated and investigated in our multiple disease models, including environmental or transgenic C elegans, Drosophila, mice disease models as well as patient cells derived human neuron and brain organoid models. These researches are conducted in close collaboration with Professor Tan Eng King, Senior Consultant, Department of Neurology, NNI@SGH as well as other local and international researchers to emphasise clinical implications and applications of our findings to make allied victory.
Our works will not only advance our understanding of disease pathogenesis, but also benefit our patients via contributions of new therapeutic drugs, diagnostic biomarker and therapeutic strategies against human neurodegeneration.
Scheme 1. Illustration of the role of LRRK2-PINK1 on TH expression and DA synthesis in DA neuronsUnder physiological conditions, LRRK2 and PINK1 form a functional balance to maintain normal TH expression and DA synthesis in DA neurons. LRRK2 promotes TH expression and DA generation, while PINK1 suppresses TH expression and DA generation. LRRK2 and PINK1 can regulate degradation of each other, thus a balance can be reached. When LRRK2 is mutated its kinase activity is increased, leading to up-regulated TH expression and increased DA generation. Increased LRRK2 kinase activity can facilitate PINK1 degradation, down regulate PINK1 level and suppress PINK1 function. This will lead to imbalance between LRRK2 and PINK1, contributing to increased TH expression, enhanced DA generation, aggravated DA oxidation and elevated DA relevant stress in DA neurons, promoting neurodegeneration. When PINK1 is mutated, kinase activity will be impaired causing LRRK2-PINK1 imbalance and disrupting TH-DA pathway, promoting DA neuron vulnerability and neurodegeneration.
Grant Support
Selected Publications in the Past Five Years
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