PhD by Research Programme (Dermatology and Skin Biology)

Research Project Title: Characterization of GSK3β Pathway in T-lymphocyte Migration and Effector Functions

Principal Investigator:

Assistant Professor Navin Kumar Verma, LKCMedicineCo-supervisor: Professor Bernhard Otto Boehm, LKCMedicine

Collaborators:

• Associate Professor Sze Siu Kwan, Newman, School of Biological Sciences 
•  Dr. Leong Khai Pang, Tang Tock Seng Hospital Singapore

Project Discription:
T-lymphocyte migration is a key element of an adaptive immune response. However, aberrant Tcell trafficking can lead to a variety of inflammatory and autoimmune disease conditions. The multi-step process of T-cell motility is precisely controlled by integrin-mediated adhesions and chemokine signals. In particular, specific interaction of the T-cell integrin LFA-1 with the ligand ICAM-1, expressed on antigen presenting cells and endothelium during inflammation, triggers a plethora of downstream signalling cascades resulting in the dynamic reorganization of cytoskeletal systems necessary for T-cell migration.

Glycogen synthase kinase 3β (GSK3β) is a highly conserved serine/threonine protein kinase, initially identified as a regulator of glycogen metabolism. Emerging evidence suggests an important role for GSK3β in cytoskeletal remodeling and cell migration. Within this context, GSK3β controls cell motility by phosphorylating cytoskeleton-associated proteins CLASP2 and ACF7, resulting in the spatial regulation of cytoskeleton. We hypothesize that GSK3β is involved in the dynamic rearrangement of T-cell cytoskeletal systems and T-cell motility. Here, we propose to characterize potential role(s) of GSK3β in the regulation of T-cell cytoskeletal systems and functional behavior of T-lymphocytes. The student will address the following three specific aims:-Aim1: Characterize the status of GSK3β activity in migrating T-cells using cutting-edge molecular, biochemical, microscopy and High Content Analysis techniques.

• Aim2: Elucidate the mechanism of GSK3β involvement in T-cell cytoskeleton remodeling byexamining its regulation of the cytoskeleton-associated proteins CLASP2 and ACF7.
• Aim3: Investigate the role(s) of GSK3β in T-cell functioning by modulating its cellular expression or activity with the use of specific inhibitors/RNA interference and utilizing multiple in vitro and in vivo model systems.

We believe, this study will uncover a novel role of GSK3β in T-cell functioning. The knowledge gained through this work will also unveil potential new therapeutic targets for a safer, selective and reversible modulation of the adaptive immune system that will have broader clinical implications. The student will gain specialized training in T-cell biology, immunology and cell signalling, with techniques to include cell culture, microscopy, small animal models, cellular, molecular, biochemical and metabolic assays. He/she will write scientific papers that will form the basis of his/her PhD thesis.

If you have questions regarding this project, please email the Principal Investigator, Assistant Professor Navin Kumar Verma at nkverma@ntu.edu.sg

Please refer to the Lee Kong Chian School of Medicine website for programme information - http://www.lkcmedicine.ntu.edu.sg/Pages/default.aspx