Therapy of thrombocytopenic disorders by chemokines

描述(申请人提供)：谱系特异性细胞因子，包括血小板生成素(TPO)，不能重建化疗或放射(化疗)引起的骨髓抑制的早期阶段，导致长期的血小板减少和出血并发症。这项建议的长期目标是证明干细胞活性趋化因子，包括基质衍生因子-1(SDF-1)、SDF-1类似物(CTCE-0214，趋化因子治疗)、成纤维细胞生长因子-4和成纤维细胞生长因子-20(CG53135，CuraGen)，通过快速募集干细胞和祖细胞，可以在放化疗诱导的骨髓抑制后恢复三系造血和血小板生成。在骨髓(BM)中，造血干细胞和祖细胞位于特定的“小生境”中，在那里它们接受分子和细胞指令，进行增殖、分化和动员到循环中。大多数干细胞定位于骨膜周围区域，称为成骨细胞壁龛。我们已经证明，另一个动态的骨髓微环境，以正弦状的骨髓内皮细胞为界，被识别为“血管利基”，支持祖细胞的分化和他们对循环的动员。骨髓的化学辐射不仅能诱导造血干/祖细胞亚群的快速凋亡，而且还会破坏骨髓的血管微环境。这会导致骨髓移植后长期的危及生命的血小板减少和植入失败。在这些研究的基础上，我们假设SDF-1、FGF-4及其类似物通过将干细胞和前体细胞从成骨细胞壁龛快速招募到血管壁龛来支持及时的造血和血小板生成的重建，从而保护患者免受威胁生命的化疗所致的骨髓抑制。此外，FGFs和血管生成因子，如血管内皮生长因子-A，通过加速骨髓血管壁龛的再生，促进了大剂量化疗辐射后的血小板生成的重建。我们将通过研究下列特定目标来验证这一假说：1)评估成纤维细胞生长因子-4、成纤维细胞生长因子-20、SDF-1和SDF-1多肽类似物(CTCE-0214)在修复放化疗后骨髓抑制后的血小板生成重建中的作用：2)确定FGFs和血管生成因子在骨髓微环境重建和再生中的作用，以对抗放化疗诱导的血小板减少症：3)评估趋化因子预处理骨髓微环境以促进化疗后骨髓移植到化疗后骨髓的植入，从而加速血小板生成恢复的可能性。我们预计SDF-1类似物CTCE-0214(趋化因子治疗)和成纤维细胞生长因子-20(CuraGen，CGS3135)的临床可用性目前正处于I期临床试验中，将为评估这些药物在改善和快速恢复化疗和放射所致的血小板减少方面的作用提供平台

DESCRIPTION (provided by applicant): 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