? ? The Principal Investigator (P.I.) of this application has completed his post-doctoral fellowship in the Division of Hematology at The Children's Hospital of Philadelphia (CHOP). This proposal describes his 5-year research plan to receive the next level of training for the development of an academic research career in the field of hematology with specific emphasis on sickle cell disease (SCD) and other hemoglobinopathies. This proposal focuses on the efficacy of the combined use of multiple drugs that complement each other in order to reduce the dose of each drug without reducing in their beneficial effects. Based on the preliminary results, P.I. will utilize the isobologram technique, a method that was developed to find the optimum therapeutic regimen, which will not only increase the efficacy but also reduce the adverse effects by reducing the dosage of each drug needed to reveal their beneficial effect. Dr. Toshio Asakura will mentor the P.l.'s scientific development. He is a recognized leader in the field of SCD, and the Director of the NHLBI SCD Reference Laboratory. He has trained several post-doctoral fellows and graduate students, many of whom have become established investigators around the country and the world. In addition, an Advisory Committee of well-established clinical/research investigators will provide scientific and career advice to the P.I. To achieve the proposed goal, the P.I. will utilize an assortment of various analytical techniques, Tg sickle mice and isobologram technique. The P.I. will investigate: 1) the effectiveness of the combined use of hydroxyurea (HU) and another type of Hb F-inducing agent in human progenitor cells to find a condition under which the combined use of these two drugs increases the synthesis of Hb F using lesser doses of each of these cytotoxic drugs, 2) the effectiveness of the combined use of HU and Nix-0699, a potent ansickling agent, in Tg sickle mice and 3) the molecular mechanism of the induction of Hb Fsynthesis by the combined use of more than two drugs. This will be the first study to utilize the isobologram technique in the rational design of combinations of therapeutic agents in SCD therapy. CHOP provides an ideal setting for training research scientists by incorporating expertise from diverse resources into a customized program. Such an environment maximizes the potential for the P.I. to establish a scientific niche from which an academic career can be constructed. ? ?
