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Juang, Lih Jiin

University of British Columbia

Both coagulation factor XII (FXII) and fibrinogen have roles in coagulation and inflammation. Modulating the activities and/or concentration of FXII and fibrinogen may have implications for both processes, as well as other interconnected (patho)physiological processes. FXII is thought to be unimportant for hemostasis and instead contributes to thrombosis, supported by the observations that FXII-deficient animals display defective thrombus formation while maintaining normal hemostasis. Despite this, FXII remains conserved across evolution. Silicates are potent activators of FXII and can be found in soil, a ubiquitous material in the environment. Thus, this led to the hypothesis that FXII can contribute to hemostasis when soil, a naturally occurring and silicate-rich material, is introduced into wounds and comes into contact with blood. This thesis showed that soil decreased clot time and blood loss in vitro and in vivo, in a FXII-dependent manner. The procoagulant activities of soil was strongly correlated with the surface concentration of silicon, representing silicate concentration in the samples. This was the first study to describe a conclusive role of FXII in hemostasis. Fibrinogen is implicated in the underlying mechanisms of multiple pathologies. Despite the experimental and therapeutic value in decreasing circulating fibrinogen for long durations, a strategy to achieve this do not exist. Gene silencing strategies such as using siRNA to degrade a target mRNA can deplete the corresponding protein from circulation for long durations. This thesis showed the development and characterization of an siRNA agent targeting fibrinogen alpha chain mRNA (siFga), which is packaged into lipid nanoparticles to enable delivery to the liver, where fibrinogen is made. siFga led to dose-dependent knockdown of circulating fibrinogen that can last for two to three weeks with a single dose. Depletion of circulating fibrinogen also led to decreased levels of platelet fibrinogen. Blood loss did not increase following tail transection in mice at the dose tested. In animal models, treatment with siFga led to attenuated acute phase response, restored macrophage/monocyte migration, and decreased the metastatic potential of tumour cells. These results show that siFga can achieve controllable knockdown of circulating fibrinogen, and that siFga may have clinical utility in diseased states.

Text

2022-10-14

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/82861

Biochemistry and Molecular Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/