Protein C pathway function in hematopoiesis

描述（由申请人提供）：本项目研究了凝血调节剂血栓调节素和天然蛋白C途径在放射损伤和化疗的造血应激反应中的先前未知的功能。我们发现内源性Thbd-蛋白C途径是致死性辐射暴露后造血功能有效恢复所必需的，并且通过药物补充蛋白C途径功能可以预防辐射诱导的骨髓衰竭导致的死亡。本研究探讨了调节血栓调节蛋白C通路这一新发现功能的细胞和分子机制。目的1确定在正常骨髓和暴露于清髓应激（放射损伤和化疗）的骨髓中表达血栓调节蛋白的相关基质细胞和造血细胞群。目的2验证骨髓间质内皮中血栓调节蛋白的表达是骨髓抑制后造血功能正常恢复所必需的假说；并且血栓调节素的这种作用是基于其以EPCR和par1依赖的方式增强tie2-血管生成素1介导的血管干细胞生态位恢复的能力。目的3研究血栓调节蛋白在造血干细胞和祖细胞中的功能作用。这种功能可能不同于其在内皮细胞中的作用，可能涉及基质巨噬细胞在骨髓抑制的造血恢复中的支持功能的调节，以及骨髓生成的细胞自主增强。目的4描述aPC的抗凝血和细胞信号功能对其治疗的贡献

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.