Protein C pathway function in hematopoiesis

描述（由申请人提供）：本项目研究了凝血调节因子血栓调节蛋白和天然蛋白C途径在造血应激反应中对辐射损伤和化疗的未知功能。我们发现，内源性Thbd-蛋白C途径是致命辐射暴露后造血有效恢复所必需的，并且蛋白C途径功能的药理学补充可预防辐射诱导的骨髓衰竭引起的死亡。本研究旨在探讨血栓调节蛋白-蛋白C通路介导这一新发现功能的细胞和分子机制。目的1鉴定在正常骨髓和暴露于清髓性应激（辐射-损伤和化学疗法）的骨髓中表达血栓调节蛋白的迄今未知的相关基质和造血细胞群体。目的2检验骨髓基质内皮中血栓调节蛋白的表达对于骨髓抑制后造血的正常恢复是必要的这一假设;并且血栓调节蛋白的这种作用是基于其以EPCR和PAR 1依赖性方式增强tie 2-angiopoietin 1介导的血管干细胞生态位恢复的能力。目的3探讨血栓调节蛋白在造血干/祖细胞中的功能作用。这种功能可能与其在内皮细胞中的作用不同，并且可能涉及调节基质巨噬细胞在骨髓抑制的造血恢复中的支持功能，以及骨髓生成的细胞自主增强。目的4阐明aPC的抗凝和细胞信号传导功能在其治疗中的作用 支持骨髓消融后造血恢复的有效性。这些研究将记录血液凝固和造血之间的新生理联系，并有可能显著影响目前对造血的理解及其药理学操作方法。

DESCRIPTION (provided by applicant): This project investigates a previously unknown function of the blood coagulation regulator Thrombomodulin and the natural protein C pathway in the hematopoietic stress response to radiation-injury and chemotherapy. We found that the endogenous Thbd- protein C pathway is required for the efficient recovery of hematopoiesis after lethal radiation exposure, and that pharmacologic supplementation of protein C pathway function prevents death caused by radiation-induced bone marrow failure. This proposal investigates the cellular and molecular mechanism mediating this newly discovered function of the Thrombomodulin-protein C pathway. Aim 1 identifies the as yet unknown relevant stromal and hematopoietic cell populations that express Thrombomodulin in normal bone marrow and in bone marrow exposed to myeloablative stress (radiation- injury and chemotherapy). Aim 2 tests the hypothesis that Thrombomodulin expression in stromal endothelium of the bone marrow is necessary for the normal recovery of hematopoiesis after myelosuppression; and that this effect of Thrombomodulin is based on its ability to augment in an EPCR- and PAR1-dependent manner the tie2- angiopoietin1-mediated recovery of the vascular stem cell niche. Aim 3 investigates the functional role of Thrombomodulin in hematopoietic stem and progenitor cells. This function is likely different from its role in endothelial cells and may involve the regulationof the supportive function of stromal macrophages in hematopoietic recovery from myelosuppression, as well as the cell-autonomous enhancement of myelopoiesis. Aim 4 delineates the contributions of aPC's anticoagulant and cell signaling functions to its therapeutic efficacy in supporting hematopoietic recovery from myeloablation. These studies will document a new physiologic connection between blood coagulation and hematopoiesis, and have the potential to significantly impact the current understanding of hematopoiesis and approaches to its pharmacologic manipulation.