The 5-year proposal is designed to prepare the candidate for an academic career in transfusion medicine. Based on clinical training in hematology-oncology, the candidate will gain maturity in scientific skills and experience in the laboratory of Dr. David Scadden at the Massachusetts General Hospital. Dr. Scadden is a well-recognized leader in stem cell research with extensive experience in mentoring trainees. The rich intellectual environment of the AIDS Research center and MGH Cancer Center is ideal for scientific development with opportunity to master a broad range of current techniques in molecular and cellular biology, particularly concepts and methods relating to in vitro and in vivo models of hematopoiesis. The proposal also includes training in transfusion medical scientists in areas of hematology, oncology, immunology and transfusion medicine will provide scientific and career guidance. The proposed research focuses on a novel seven transmembrane G protein-coupled chemokine receptor, SCGPRL. Recent work in the Scadden laboratory showed that SC-GPRI expression is highly restricted to quiescent hematopoietic stem cells (HSC) and ectopic expression of SC-GPR1 confers stem cell phenotype including quiescence and ability to home and engraft in a in vivo mouse transplant model. The proposed project is based on the hypothesis that SC-GPRI expression contributes significantly to mechanisms of HSC quiescence, homing and engraftment. Better defining these mechanisms will lead to improved techniques for HSC manipulation for therapeutic use.
The specific aims i nclude: 1. Establishing targeted disruption of SC-GPR1 gene to engineer -/and +/mice, 2. Characterizing the effect of SC-GPRI expression modulation using neutralizing antibody, antisense inhibition and overexpression strategies in addition to the -/- and +/- mice, and 3. Defining the role of SC-GPR1 in HSC homing and engraftment using mouse transplantation models.
