Protein C pathway function in hematopoiesis

蛋白 C 通路在造血中的功能

• 批准号: 9229562
• 负责人: Hartmut Karl-Heinz Weiler
• 金额: $ 41.75万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-09 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9229562
• 关键词: Animal Model; Anticoagulants; Anticoagulation; Biological; Blood Coagulation Factor; Blood Vessels; Blood coagulation; Bone Marrow; Bone Marrow Purging; Bone Marrow Transplantation; Cause of Death; Cells; Coagulation Process; Cytotoxic Chemotherapy; Data; Dose; Endothelial Cells; Endothelium; Exposure to; F2R gene; F8 gene; Flow Cytometry; Fluorouracil; Genetic; Goals; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Histology; Injury; Knowledge; Link; Measures; Mediating; Modality; Molecular; Mus; Myelopoiesis; Myelosuppression; Pancytopenia; Pathway interactions; Patients; Pattern; Pharmacology; Physiological; Population; Protein C; Radiation; Radiation Injuries; Radiation exposure; Radiation therapy; Radioprotection; Reagent; Receptor Signaling; Recombinants; Recovery; Resistance; Role; Signal Transduction; Stem cells; Stress; Stromal Cells; Supplementation; System; Testing; Therapeutic Effect; Therapeutic Uses; Thrombomodulin; Treatment Efficacy; Variant; Whole Organism; activated protein C receptor; base; biological adaptation to stress; chemotherapy; cytotoxic; efficacy testing; factor V Leiden; macrophage; mouse model; prevent; protective effect; public health relevance; radiation recovery; reconstitution; response; response to injury; stem cell niche

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.

描述（由申请人提供）：该项目研究了凝血调节剂血栓调节蛋白和天然蛋白 C 途径在对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途径对于致死性辐射暴露后造血功能的有效恢复是必需的，并且通过药物补充蛋白C途径功能可以预防由辐射引起的骨髓衰竭引起的死亡。该提案研究了介导血栓调节蛋白-蛋白 C 途径这一新发现功能的细胞和分子机制。目标 1 鉴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迄今未知的相关基质细胞和造血细胞群。目标 2 验证了以下假设：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功能的正常恢复是必需的；血栓调节蛋白的这种作用是基于其以 EPCR 和 PAR1 依赖性方式增强 ti2- 血管生成素 1 介导的血管干细胞生态位恢复的能力。目标 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。该功能可能不同于其在内皮细胞中的作用，并且可能涉及基质巨噬细胞在骨髓抑制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。目标 4 描述了 aPC 的抗凝和细胞信号传导功能对其治疗的贡献 支持清髓造血恢复的功效。这些研究将记录凝血和造血之间新的生理联系，并有可能显着影响目前对造血及其药理操作方法的理解。

项目成果

Variable phenotypic penetrance of thrombosis in adult mice after tissue-selective and temporally controlled Thbd gene inactivation.

组织选择性和时间控制 Thbd 基因失活后，成年小鼠血栓形成的可变表型外显率。

• DOI: 10.1182/bloodadvances.2017005058
• 发表时间: 2017
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: vanMens,ThijsE;Liang,Hai-PoH;Basu,Sreemanti;Hernandez,Irene;Zogg,Mark;May,Jennifer;Zhan,Min;Yang,Qiuhui;Foeckler,Jamie;Kalloway,Shawn;Sood,Rashmi;Karlson,CarenSue;Weiler,Hartmut
• 通讯作者: Weiler,Hartmut