(provided by candidate): The long-term goal of the candidate is to apply innovative image-guided delivery techniques to the field of in vivo tissue engineering for patients with peripheral arterial occlusive disease. The specific focus of this proposal will concentrate on the method of gene delivery to induce therapeutic arteriogenesis. To realize this goal, the candidate, has developed a multi-disciplinary mentored-based research career development plan which provides training in 2 realms: 1) in vivo tissue engineering and 2) professional skills needed to launch a career as an independent clinical scientist. This didactic and structured training program, combined with the candidate's clinical skills as an Interventional Radiologist, complements the following research proposal. Therapeutic arteriogenesis is the administration of exogenous growth factors in order to augment the body's natural arteriogenic response. It is a promising therapy for patients with severe chronic limb ischemia who are not amenable to conventional revascularization and the only option is amputation. Hypoxia-inducible factor 1 (HIF-1) functions as a """"""""master switch"""""""", regulating the expression of multiple arteriogenic growth factors. We have created an endovascular rabbit hindlimb ischemia model and tested the intramuscular (IM) administration of an adenovirus encoding HIF-1alpha that was developed at our institution. Our preliminary studies show transient gene expression, which results in a robust arteriogenic response that is attenuated at later time points. Previous investigators have attributed this to the immune response mounted against the adenoviral vector. We propose to study non-viral methods of delivery, in order to circumvent immunogenicity issues. Although plasmid administration has demonstrated encouraging results in animal studies, clinical trials have shown marginal efficacy. The main limitation of this technique is low transfection efficiency as the plasmid is rapidly degraded by extracellular nucleases. Many believe that sustained growth factor production is necessary to induce a persistent arteriogenic effect. To that end, we have developed a cationic polymer that slowly releases plasmid overtime, prevents its degradation by nucleases and increases intramuscular transfection efficiency compared to plasmid alone. The guiding hypothesis of this proposal is that sustained intramuscular HIF-1 plasmid (HIF) delivery is necessary for a persistent arteriogenic effect in our endovascular model of hindlimb ischemia.
Specific aim 1 determines the effect on perfusion of IM injection of HIF at a single time point.
Specific aim 2 investigates the effect of sequential (two different time points) IM administrations of HIF on perfusion.
Specific aim 3 examines the effect on hindlimb perfusion following the IM administration of HIF in a controlled-release form at a single time point. These projects and career development plans will provide the resources, collaborative relationships, and academic foundation of which the candidate will build a successful career as an independent clinical scientist.
| Korosoglou, Grigorios; Weiss, Robert G; Kedziorek, Dorota A et al. (2008) Noninvasive detection of macrophage-rich atherosclerotic plaque in hyperlipidemic rabbits using ""positive contrast"" magnetic resonance imaging. J Am Coll Cardiol 52:483-91 |
| Korosoglou, Grigorios; Tang, Lijun; Kedziorek, Dorota et al. (2008) Positive contrast MR-lymphography using inversion recovery with ON-resonant water suppression (IRON). J Magn Reson Imaging 27:1175-80 |
| Korosoglou, Grigorios; Shah, Saurabh; Vonken, Evert-Jan et al. (2008) Off-resonance angiography: a new method to depict vessels--phantom and rabbit studies. Radiology 249:501-9 |
| Korosoglou, Grigorios; Gilson, Wesley D; Schar, Michael et al. (2007) Hind limb ischemia in rabbit model: T2-prepared versus time-of-flight MR angiography at 3 T. Radiology 245:761-9 |
