The Comprehensive Sickle Cell Center (CSCC) at the Los Angeles County+USC Medical Center: represents the continued collaboration of an investigative group that has devoted a substantial portion of their careers since 1972 towards basic, applied, and clinical research in sickle cell disease. The overall focus and unifying theme of this research continues to be the pathophysiology, clinical consequences and treatment of vascular events in sickle cell disease. Vascular disorders, including vascular occlusion, represent the most important cause of morbidity and mortality in this disease, yet their pathophysiology is still incompletely understood and their treatment remains Largely unsatisfactory. Determining possible genetic bases for the variable clinical severity of the disease and genetic approaches to therapy are also of central interest, yet again our understanding in these areas is less than satisfactory. In the current proposal, this group of investigators will continue to be concerned with vascular disorders in sickle cell disease; in addition, we have incorporated genetics-based components seeking to understand the variable clinical severity and to develop novel therapeutic approaches in this disease. The program described herein consists of five hypothesis-based projects (Projects 1-5), and four Cores (Administrative, Clinical/Patient Service, Laboratory, Animal) that support these projects and the overall objectives of the Center. Project 1, our Collaborative Clinical Research Component, seeks to examine relations among polymorphisms in specific blood groups and clinical severity; Project 2 examines critical elements of the pathophysiology of pulmonary hypertension; Project 3 seeks to determine the ability of anti-inflammatory agents to block hypoxia-induced decreases of blood flow; Project 4 explores genetic therapy for sickle cell disease via examining the potential benefits of self-inactivating lentiviral vectors; Project 5 seeks to define in detail the molecular mechanisms that lead to the accumulation of monocytes and PMN in the alveolar compartment. We strongly support the Inter-Center Collaborative concept and the Sickle Cell Scholar program, and believe that successful completion of our Projects will yield important new information for improved patient care.