Jessica Lin

BME PhD Thesis Proposal Presentation

Date: 3/9/2020

Time: 2PM

Location: Whitaker McIntire Conference Room 3115

Committee members:

Wilbur Lam, MD, PhD (Advisor)

Anton Bryksin, PhD

Erik Dreaden, PhD

MG Finn, PhD

Karmella Haynes, PhD

Title: Engineered bacterial surface display of fibrinolytic proteins for treatment of thrombotic disease

Abstract:

Abnormal blood clotting causes thromboembolic disease including ischemic stroke and myocardial infarction, which are two of the leading causes of death worldwide. Currently, one of the main treatments for acute thromboembolic disease is fibrinolytic therapy. Fibrinolytic therapy is systemic or local administration of a plasminogen activator to digest the blood clot. However, fibrinolytic therapy has a short half-life and can cause severe side effects including off-target bleeding and immunogenic response. Thus, there is a need for improved fibrinolytic therapy that improves the half-life, decreases off-target effects, and reduces the treatment time. I propose to use engineered bacteria cells to express fibrinolytic protein on the cell surface for treatment of thromboembolic disease. Synthetic biology and live engineered cells have great potential for therapeutic application. Cells can respond to their environment and be easily controlled to deliver a constant source of therapeutic proteins. Engineered cells have already been used in the clinic to treat diseases such as cancer and blood disorders. Bacteria, particularly E. coli, are a very well-characterized system for heterologous protein expression. With the increased interest in bacterial presence in the human body, engineered bacteria are also being put forth as therapeutic cells to treat diseases from cancer to diabetes. For my thesis, I hope to apply synthetic biology techniques to a solve a clinical problem by engineering bacteria to express fibrinolytic proteins and digest blood clots. The goal of this work is to develop, characterize, and optimize an E. coli surface display system to express the fibrinolytic protein streptokinase for treatment of thrombotic diseases. To minimize off-target effects of treatment, the bacteria will also be engineered to display fibrin-targeting capabilities and conditionally release the streptokinase at the site of the blood clot.