Protein C pathway function in hematopoiesis

描述(由申请人提供)：本项目研究凝血调节因子血栓调节蛋白和天然蛋白C途径在辐射损伤和化疗的造血应激反应中的未知功能。我们发现，内源性Thbd-蛋白C途径是辐射致死后有效恢复造血所必需的，而蛋白C途径功能的药理补充可以防止辐射诱导的骨髓衰竭引起的死亡。这项建议研究了调节血栓调节蛋白-蛋白C途径这一新发现功能的细胞和分子机制。目的1鉴定在正常骨髓和清髓性应激(放射损伤和化疗)下骨髓中表达血栓调节蛋白的相关基质和造血细胞。目的2验证血栓调节蛋白在骨髓抑制后骨髓间质内皮细胞中的表达是骨髓抑制后正常造血恢复所必需的假说，并且血栓调节蛋白的这种作用是基于其以EPCR和PAR1依赖的方式增强Tie2-Angiopoietin1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、祖细胞中的功能作用。这一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后的造血恢复中的支持功能的调节，以及细胞自主促进骨髓生成。目的4阐明APC的抗凝血剂和细胞信号功能在其治疗中的作用 支持骨髓清除术后造血功能恢复的疗效。这些研究将证明凝血和造血之间的一种新的生理学联系，并有可能显著影响目前对造血的理解及其药物操作的方法。

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.