Therapy of thrombocytopenic disorders by chemokines

描述（由申请方提供）：谱系特异性细胞因子，包括血小板生成素（TPO），不能重建化疗或放疗（化疗-放疗）诱导的早期骨髓抑制，导致长期血小板减少和出血并发症。本提案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，Chemokine Therapeutics）、FGF-4和FGF-20（CG 53135，CuraGen），通过快速募集干细胞和祖细胞，可以在化疗-放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）内，造血干细胞和祖细胞驻留在限定的“小生境”中，在那里它们接收用于增殖、分化和动员到循环的分子和细胞指令。大多数干细胞定位于骨内膜周围区域，称为成骨细胞龛。我们已经表明，另一个动态的BM微环境，划定的窦BM内皮细胞，确定为“血管生态位”，支持祖细胞的分化和他们的动员循环。骨髓的化学-辐射暴露不仅诱导造血干细胞和祖细胞亚群的快速凋亡，而且还损害骨髓的血管微环境。这导致骨髓移植后长期危及生命的血小板减少症和植入失败。基于这些研究，我们假设SDF-1、FGF-4及其类似物通过从成骨细胞龛向血管龛快速募集干细胞和祖细胞来支持造血和血小板生成的及时重建，从而保护免受危及生命的化学辐射诱导的骨髓抑制。此外，FGF和血管生成因子，如VEGF-A，通过加速BM血管生态位的再生，有助于高剂量化疗-放疗后血小板生成的重建。本研究将通过以下几个方面的研究来验证这一假设：1）评估FGF-4、FGF-20、SDF-1及其肽类似物的潜力（CTCE-0214）在化疗-放疗诱导的骨髓抑制后恢复血小板生成重建：2）确定FGF和血管生成因子在BM血管生态位的重建和再生中的作用，以保护免受化疗。辐射诱导的血小板减少症：3）评估用趋化因子预调节BM微环境以增强BM移植到化学辐射处理的BM中后的植入，从而加速血小板生成恢复的潜力。我们预计，目前正在I期临床试验中评估的SDF-1类似物CTCE-0214（趋化因子治疗剂）和FGF-20（CuraGen，CGS 3135）的临床可用性将为评估这些药物在改善和快速恢复化疗和放疗诱导的血小板减少症中的作用提供平台

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