DESCRIPTION: It has been known that increased levels of HbF reduce the clinical severity and the number of painful episodes in individuals with sickle cell disease. This became apparent when it was observed that newborns do not show symptoms of the disease until the switching of HbA occurs and the HbA containing the mutant beta globin chain becomes the predominate hemoglobin synthesized. The immediate goal of the research plan is to delineate the molecular mechanisms by which pharmacologic agents augment the variable but persistent expression of the fetal hemoglobin. The long-term goal is to integrate the data into a program of research aimed at creating effective interventions to ameliorate the associated complications of sickle cell disease. There are two specific aims defined in the proposed research effort. Specific aim #1 is to determine the similarities and differences in the HEL cells following in vitro exposure and pharmacologic induction by sodium phenylbutyrate, hydroxyurea and 5-azacytidine alone and in combination. This specific aim will build on work previously done by others and including the laboratory in which the applicant will perform her studies. The applicant will learn the associated problems of tissue culture studies, how to handle pharmacologic studies and to be able to interpret the data. This part of the application would have been strength if the applicant would have given the reviewer an idea of the expected results. Specific aim #2 is to test the genes identified in aim #1 during the differentiation of CD34+ cells. The methods to be used during the performance of the aim #2 include the isolation and induction of the target cell of interest, CD34+ positive cells. RESEARCH PLAN