Understanding of a Neurophenotype in Hemophilia A

The long-term goal of my work is to improve treatment options for patients with hemophilia and other heritable bleeding disorders. The goal of my current research is to understand the impact of factor VIII deficiency on brain structure and function as well as determine the mechanism behind these changes. In our previous studies investigating survival of hemophilia A mice, we observed unusual behavior. After investigation we discovered an anxiety-like phenotype as demonstrated by increased time in the periphery on open field and increased time in the dark on light/dark testing. In order to accomplish the goal of the current proposal, we will utilize quantitative neuroimaging techniques to assess change in brain structure including intracranial volume and we will measure glial activation and neuroinflammation to determine the mechanism of the underlying neurophenotype in hemophilia A mouse model. In addition, we will determine if factor VIII replacement via our established gene transfer methods reduces or resolves the anxiety-like behavior in the hemophilia A mouse model. As part of the Hemophilia and Thrombosis Center at Iowa, I have an intimate knowledge of the up and coming therapies in the field. I have generated the preliminary data including behavior studies with hemophilia A mice. Published data on piggyBac transposon liver-transduction including tissue cell work and in vivo testing demonstrates the feasibility of long-term factor VIII replacement in the hemophilia A mouse model . As an early stage investigator, I had strong mentorship under the guidance of Drs. Paul McCray and Steven Lentz to complete my post-doctoral research and training in gene therapy and hemophilia research. I have extensive experience with the phenotypic studies in mouse models including behavior studies, vector delivery systems both in vivo and in vitro, and multiple coagulation antigen and activity assays.