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Jiexi Liao
BME PhD Proposal
December 14, 2017, 9-11 AM
McIntire Conference Room (3115), Whitaker Building
Committee:
Advisor: Cheng Zhu, PhD
Georgia Institute of Technology, Department of Biomedical Engineering
Shuichi Takayama, PhD
Georgia Institute of Technology, Department of Biomedical Engineering
Manu O. Platt, PhD
Georgia Institute of Technology, Department of Biomedical Engineering
Brian G. Petrich, PhD
Emory University, Department of Pediatrics
Shaun P. Jackson, PhD
University of Sydney, Heart Research Institute
Title:
Mechanically regulated hyper-reactivity of platelets in diabetes: a close look at binding-signaling-binding
Abstract:
Diabetes affects 422 million people globally and the prevalence is growing. Cardiovascular complications from atherothrombosis are the primary cause of diabetes-related death largely due to the exaggerated thrombotic response. Diabetic patients are typically less responsive to conventional anti-coagulant and anti-platelet therapies that target the biochemical pathways of thrombosis, which further increases the risk of morbidity and mortality. Evidence suggests that biomechanical pathways of platelets are markedly dysregulated in diabetes. This proposal aims to identify and characterize key players in the platelet mechanotransduction loop (binding-signaling-binding) and how their functional balance might be tipped in diabetes. Mechanosensors, such as GPIb and integrin GPIIbIIIa on platelets, can upregulate secondary messengers when binding to ligand under shear; the secondary messengers may initiate signaling cascade that would induce talin, a cytoplasmic adaptor protein, to link cytoskeleton to and activate integrins, resulting in platelet activation. The working hypotheses are 1) diabetic platelets, through GPIIbIIIa mechanosensing, are more reactive to increasing mechanical stimuli, and 2) the shear modulation of cGMP, a generally anti-thrombotic secondary messenger, is dysfunctional in diabetes, and 3) platelet talin is dysregulated in diabetes; disruption of interactions between the talin head and integrin GPIIbIIIa tail that are crucial for platelet adhesion and aggregation could eliminate the phenotype of diabetic platelets.
