Thalassemia and sickle cell disease are important red cell disorders due to inherited deficiencies in human hemoglobins. The objective of this research project has been to investigate hemoglobinopathies using a variety of methods with the ultimate aim of applying the findings to the care of affected patients. In recent years, the studies have emphasized applications of molecular biology to the evaluation of the genetic diversity of thalassemia and other hemoglobinopathies and to the examination of the control of expression of normal and abnormal human globin genes. In the past few years, an additional direction for investigation has arisen from the desire to isolate clones for proteins expressed in megakaryocytes, including PF4, GPIIb and GPIIIa, to examine hematopoietic differentiation and genetic defects of platelets. The studies proposed include examination of thalassemia variants, investigation of the developmental switch from fetal to adult hemoglobin, analysis of DNA sequences involved in expression of genes for platelet proteins, and an elucidation of molecular defects in patients with thrombasthenia from a variety of ethnic backgrounds. The studies of thalassemia variants will include deletions in the globin gene clusters, a continuation of the investigation of the silent carrier of beta thalassemia, and other mutations, particularly those from the Near East. Research on the developmental switch will involve variations in DNA sequences that affect the expression of the two normal gamma globin loci. Studies of gene expression in megakaryocytes will include analysis of the structure of GPIIb, GPIIIa, and PF4 genomic clones. Patients with thrombasthenia, a bleeding disorder due to deficiencies in the GPIIb-GPIIIa platelet membrane complex that binds fibrinogen and other adhesive proteins, from a variety of ethnic backgrounds will be studied in order to clarify the exact mutations in DNA responsible for this disease. The proposed studies should provide further information about diseases due to mutations in genes that are characteristic of specific hematopoietic cell lineages such as thalassemia, sickle cell disease, and thrombasthenia.
Showing the most recent 10 out of 36 publications