The long-term goals of this project are to elucidate the role and regulation of chemokines and chemokine receptors (CKR) that are involved in the homing and engraftment of hematopoietic stem/progenitor cells (HSPC) during bone marrow transplant (BMT) and, by modulating the migration or homing of HSPC, to enhance HSC engraftment functions. BMT has been widely performed in an increasing number of clinical settings. Extensive efforts have led to our understanding of the HSPC phenotypes and biological activity in vitro and in vivo. HSPC migrate or home to the BM after transplantation to engraft, expand and differentiate. The mechanism of HSC homing and engraftment in the bone marrow, however, is poorly understood. I hypothesize that interaction of specific chemokines in the bone marrow with CKR on HSPC regulates the specific homing. Altering the interaction between these chemokines and CKR will provide an efficient means to modulate these activities during BMT. We have recently developed a novel genetic system to inhibit function of CKR with their specific chemokine ligand fused to the HIV-1 Vpu domain that traps and degrades the CKR in the ER (degrakines). I propose to establish a novel genetic model to define and characterize the CKR on HSC progenitor cells that are required for their homing and engraftment in the bone marrow. We will confirm the homing and engraftment activity of the defined CKR with CKR mutant mice or with specific antibodies and antagonists after BMT. In addition, ectopic expression of the putative CKR will be performed to enhance homing and engraftment of HSPC. The defined CKR will shed light on the development of novel BMT protocols with enhanced HSC engraftment. The degrakine mediated genetic system will also be useful in dissecting cell migration during other biological processes. Specifically, we will develop a novel genetic system to systemically define CKR involved in homing of HSPC cells to and in engraftment in the BM. By the end of the project, we will 1) develop a novel """"""""Degrakine"""""""" system to analyze most or all of the CKR with known chemokine ligands expressed in the BM. 2) We will define the CKR on HSC that are required for BM homing and engraftment. 3) We will test possible modulation of CKR activity to improve BMT. The findings will open new avenues in understanding the biology of chemokines and CKR in BMT, and for developing therapeutics to improve HSPC engraftment. The novel (Degrakine) genetic approach will also be applicable to the analysis of cell migration in other biological processes such as heart and lung functions, as well as mature hemato-lymphoid cells.
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