This is a competitive renewal application of P01 HL095489, which provides support for a coordinated, multi- disciplinary program project entitled Molecular mechanisms of blood cell transfusion. The long-term thematic objective of this research program is to develop more efficient and effective Transfusion Medicine support for patients undergoing stem cell transplantation. Patients in the peri-transplant period require significant transfusion support (including red blood cells, platelets and granulocytes) because of the transplant-related bone marrow (BM) dysfunction state. In this application we hypothesize that bone marrow dysfunction is caused in part by a compromised hematopoietic stromal niche (project 1); that engraftment is limited by the quantity of transplantable hematopoietic stem/progenitor cells (HSPC) (project 2); and that the efficacy of granulocyte transfusions towards the treatment of peri-transplant (bacterial and yeast) infections can be optimized (project 3). The principal investigators, project leaders, and core leaders are all faculty of the Joint Program in Transfusion Medicine (JPTM) at Harvard Medical School. Project 1, Dr. Leslie Silberstein will elucidate the dynamic role of CXCL12 expressing stromal niche cells in hematopoiesis during inflammatory stress. This study will lead to new therapeutic approaches for hematopoietic regeneration in bone marrow dysfunction states, which require significant blood product support. Project 2, Dr. Li Chai will try to understand hematopoietic stem progenitor cell properties by investigating the interaction between transcription factors and epigenetic modulators (chromatin modifiers). This project will focus on SALL4, a zinc-finger transcription factor that interacts with both activation and repression epigenetic complexes. The hypothesis is that a newly identified SALL4 activation pathway is important for CD34+ HSPC expansion. Project 3, Dr. Hongbo Luo will study cell signaling in granulocyte transfusion. The ultimate goal is to identify cellular and molecular events that can improve granulocyte performance after transfusion. They try to achieve this by elevating intracellular PtdIns(3,4,5)P3 signaling via targeting InsP6K1, an enzyme responsible for the synthesis of InsP7, a cytosolic molecule that negatively regulates PtdIns(3,4,5)P3 signaling. The three supporting cores are: Administrative Core, Animal Core, and a Cytometry Core. The Administrative Core will oversee and coordinate the day-to- day scientific and fiscal operation of the Program. The Cytometry Core will provide a cost-effective, centralized resource for the use of antibody based cellular pre-enrichment, flow cytometry based cell analysis and purification, as well as imaging and quantitative analysis of cellular and subcellular criteria within tissues using laser scanning cytometry (LaSC) technology. The Experimental Animal Core will assist with transgenic and knockout mouse production, multi-trait breeding, and animal husbandry. Collectively, this program will yield significant insight and information that will directly translate into optimizatin of Transfusion Medicine support of patients requiring transfusion in the peri-transplant setting. (End of Abstract) PROJECT 1: INFLAMMATORY MODULATION OF CXCL12 EXPRESSING NICHE CELLS IN BONE MARROW (SILBERSTEIN, LESLIE ERIC)
Transfusion Medicine has evolved into an important clinical practice and science related to the processing and therapeutic use of blood cells. Optimizing blood cell support for specific patient groups and clinical settings is an emerging priority in transfusion medicine. Patients undergoing bone marrow transplantation experience a period of bone marrow failure, which often requires significant transfusion support to replace low numbers of red blood cells, platelets and/or granulocytes. Ultimately, the goal of this research program is to develop more efficient and effective Transfusion Medicine related strategies for the benefit of the blood transfusion recipient.
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