Lineage-specific cytokines, including thrombopoietin (TPO), fail to reconstitute early phases of myelosuppression induced by chemotherapy or irradiation (chemo-radiation), leading to prolonged thrombocytopenia and bleeding complications. The long-term objective of this proposal is to demonstrate that stem cell active chemokines, including Stromal Derived Factor-1 (SDF-1), SDF-1 analogue (CTCE-0214, Chemokine Therapeutics), FGF-4 and FGF-20 (CG53135, CuraGen), by rapid recruitment of stem and progenitor cells could restore tri-lineage hematopoiesis and thrombopoiesis after myelosuppression induced by chemo-radiation. Within the bone marrow (BM), hematopoietic stem and progenitor cells reside in defined """"""""niches"""""""" where they receive molecular and cellular instructions for proliferation, differentiation and mobilization to the circulation. The majority of stem cells are localized to the periendosteal region referred to as the osteoblastic niche. We have shown that another dynamic BM microenvironment, demarcated by the sinusoidal BM endothelial cells, identified as the """"""""vascular niche"""""""", supports differentiation of progenitors and their mobilization to the circulation. Chemo-radiation exposure to the BM not only induces rapid apoptosis of subsets of hematopoietic stem and progenitor cells, but also damages the BM's vascular microenvironment. This leads to long-lasting life-threatening thrombocytopenia and engraftment failure after BM transplantation. Based on these studies, we hypothesize that SDF-1, FGF-4 and their analogues by rapid recruitment of stem and progenitor cells from the osteoblastic niche to the vascular niche support timely reconstitution of hematopoiesis and thrombopoiesis thereby protecting against life-threatening chemo-radiation induced myelosuppression. In addition, FGFs and angiogenic factors, such as VEGF-A, by accelerating the regeneration of the BM's vascular niche contribute to the reconstitution of thrombopoiesis after high doses of chemo-radiation. This hypothesis will be tested through studying the following specific aims: 1) Assess the potential of FGF-4, FGF-20, SDF-1 and SDF-1 peptide analogue (CTCE-0214) in restoring thrombopoietic reconstitution after chemo-radiation induced myelosuppression: 2) Determine the role of the FGFs and angiogenic factors in reconstruction and regeneration of BM's vascular niche to protect against chemo-radiation induced thrombocytopenia: 3) Evaluate the potential of pre-conditioning the BM microenvironment with chemokines to enhance engraftment after BM transplantation into the chemo-irradiated treated BM, thereby accelerating thrombopoietic recovery. We anticipate that clinical availability of the SDF-1 analogue, CTCE-0214 (Chemokine Therapeutics), and FGF-20 (CuraGen, CGS3135) that are currently being evaluated in phase I clinical trials, would provide the platform for assessing the role of these agents in amelioration and rapid restoration of thrombocytopenia Induced by chemotherapy and irradiation ? ?
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