This Career Development Award proposal is designed to allow the candidate to develop the skills needed to become an outstanding investigator in the translational science of ischemic stroke treatment, and ultrasound-enhanced thrombolysis (UET). Stroke is a major medical problem in the U.S. and a leading cause of death and disability. Currently, the only FDA approved therapy is the administration of tissue plasminogen activator (tPA) within 3 hours of stroke onset. There are many contraindications and side effects to this treatment including intra-cerebral hemorrhage (ICH). Therefore, there is great interest in adjunctive therapies such as UET, GP llb-llla inhibitors, ultrasound-assisted targeted drug delivery agents, and hypothermia that may improve stroke treatment and possibly reduce side effects of thrombolytic therapy. Improved effectiveness and/or greater safety in the use of thrombolytic therapy would provide a great benefit to the public health, as the incidence of ischemic stroke is increasing as the overall population ages. The objectives of this proposal are to 1) develop expertise and didactic knowledge in neuroscience, ultrasound and microscopic imaging, 2) gain familiarity with the clinical treatment of acute stroke, and (3) study the effects of adjunctive therapies on tPA thrombolysis in an in-vitro human clot model. The candidate proposes a 5-year career development program with contributors funded in the area of stroke research. The contributors to this proposal are respected experts in Neurology, Biochemistry and Biomedical Engineering, which are areas directly relevant to the proposal. The plan focuses on enhancing the knowledge required to implement basic and translational research in ultrasound-assisted thrombolysis, ultrasound contrast agents and hypothermia as potential adjunctive treatments for stroke. This includes coursework, independent study and specific clinical training rotations. Training in the responsible conduct of research and mentored experiences in the clinical treatment of acute ischemic stroke are planned. The proposed research will examine the effects of GP llb-llla inhibitors, ultrasound contrast agents and hypothermia on ultrasound enhanced tPA thrombolysis. A unique microscopic visualization technique will be employed to observe in-vitro human clot dissolution during lytic treatment in real-time. This innovative technique allows the direct measurement of clot size while it undergoes lysis. The efficacy of adjunctive therapies will be assessed via this microscopic quantification of clot dissolution. The overall hypothesis is that ultrasound improves the thrombolytic efficacy of tPA with or without adjunctive therapies. Such data would be of tremendous use in planning future in-vitro, in-vivo and clinical trials studying these adjunctive therapies. The results of this work could easily be taken from """"""""bench to bedside"""""""" by virtue of the candidate's ongoing collaboration with Greater Cincinnati/Northern Kentucky stroke team. ? ? ?
| Kandadai, Madhuvanthi A; Meunier, Jason M; Hart, Kimberley et al. (2015) Plasmin-loaded echogenic liposomes for ultrasound-mediated thrombolysis. Transl Stroke Res 6:78-87 |
| Meunier, Jason M; Wenker, Evan; Lindsell, Christopher J et al. (2013) Individual lytic efficacy of recombinant tissue plasminogen activator in an in vitro human clot model: rate of ""nonresponse"". Acad Emerg Med 20:449-55 |
| Meunier, Jason M; Holland, Christy K; Porter, Tyrone M et al. (2011) Combination treatment with rt-PA is more effective than rt-PA alone in an in vitro human clot model. Curr Neurovasc Res 8:305-12 |
| Shaw, George J; Meunier, Jason M; Lindsell, Christopher J et al. (2010) Making the right choice: optimizing rt-PA and eptifibatide lysis, an in vitro study. Thromb Res 126:e305-11 |
| Shaw, George J; Meunier, Jason M; Huang, Shao-Ling et al. (2009) Ultrasound-enhanced thrombolysis with tPA-loaded echogenic liposomes. Thromb Res 124:306-10 |
| Meunier, Jason M; Holland, Christy K; Pancioli, Arthur M et al. (2009) Effect of low frequency ultrasound on combined rt-PA and eptifibatide thrombolysis in human clots. Thromb Res 123:528-36 |
| Shaw, George J; Meunier, Jason M; Lindsell, Christopher J et al. (2008) Tissue plasminogen activator concentration dependence of 120 kHz ultrasound-enhanced thrombolysis. Ultrasound Med Biol 34:1783-92 |
| Meunier, Jason M; Holland, Christy K; Lindsell, Christopher J et al. (2007) Duty cycle dependence of ultrasound enhanced thrombolysis in a human clot model. Ultrasound Med Biol 33:576-83 |
| Shaw, George J; Dhamija, Ashima; Bavani, Nazli et al. (2007) Arrhenius temperature dependence of in vitro tissue plasminogen activator thrombolysis. Phys Med Biol 52:2953-67 |
