MOLECULAR & CELLULAR MECHANISMS IN TRANSFUSION MEDICINE

描述(由申请人提供)： 这是HL-44612项目资助计划16-20年度的修订后的竞争续签申请，该计划为对输血医学领域重要的分子和细胞机制进行协调的、多学科的调查提供支持-这一学科尽管对国家健康具有明显的重要性，但历史上在培训和研究资源方面一直代表不足。我们的申请反映了十多年来项目负责人之间持续的、密切的合作关系，他们仍然致力于以血液和血管细胞生物学为中心的相关研究项目。在第一个项目中，Peter和Debra Newman提出了四个相互关联的目标，旨在加深我们对调节血小板激活和黏附的细胞表面受体和相关信号通路的理解。在第二个项目中，Dick Aster建议继续他对暴露于阿昔单抗或类似配体的GPIIb/IIIa抑制剂的患者中导致急性血小板破坏的预先存在的、“自然发生的”抗体的研究，以及 可能对其他免疫紊乱有重要影响。第三个项目由谢丽尔·希勒里领导，旨在确定凝血途径如何导致镰状细胞诱导的器官损伤，并探索限制血管闭塞的急性发作和伴随的慢性器官损伤的潜在疗法。第四个项目由Bob Montgomery领导，继续探索VWF生物合成的结构要求，为治疗严重血友病A患者的全新替代疗法方法奠定基础。共享仪器核心公司将继续为DNA序列分析、肽合成、显微镜/数字图像分析、组织学、流式细胞仪和细胞分选、Biacore分析和单抗生产提供集中式仪器和专业知识。转基因/基因敲除小鼠核心将协助载体设计、转基因小鼠生产、胚胎干细胞生长和转基因、育种和畜牧业。总而言之，这些多重合作所提供的想法、试剂和专业知识的整体科学协同作用，应该能够使这项输血医学研究计划项目能够增进我们对血液和血管细胞生物学的理解，并将所取得的成果应用于治疗血液疾病和提高输血治疗的有效性。

DESCRIPTION (provided by applicant): This is a revised competitive renewal application for years 16-20 of Program Project Grant HL-44612, which provides support for a coordinated, multi-disciplinary investigation of molecular and cellular mechanisms important to the field of transfusion medicine - a discipline that, despite its obvious importance to the nation's health, has historically been underrepresented in both training and research resources. Our application reflects ongoing, close collaborative ties that have existed amongst the Project Leaders for more than a decade, and who remain committed to interrelated research projects centered around the biology of blood and vascular cells. In the first Project, Peter and Debra Newman propose four interrelated aims that seek to further our understanding of the cell surface receptors and associated signaling pathways that regulate platelet activation and adhesion. In the second Project, Dick Aster proposes to continue his investigation of pre-existing, "naturally-occurring" antibodies that cause acute platelet destruction in patients exposed to abciximab or ligand-mimetic GPIIb/IIIa inhibitors, and may have important implications for other immune disorders. The third Project, led by Cheryl Hillery, seeks to define how blood coagulation pathways contribute to sickle cell-induced organ damage, and to explore potential therapies that limit both acute episodes of vaso-occlusion and the accompanying chronic organ damage. The fourth Project, led by Bob Montgomery continues to explore the structural requirements for VWF biosynthesis that lay the foundation for an entirely novel replacement therapy approach for the treatment of patients with severe hemophilia A. The Shared Instrumentation Core will continue to provide centralized instrumentation and expertise for DNA sequence analysis, peptide synthesis, microscopy/digital image analysis, histology, flow cytometry and cell sorting, BIAcore analysis, and monoclonal antibody production. The Transgenic/Knockout Mouse Core will assist with vector design, transgenic mouse production, embryonic stem cell growth and transfection, breeding, and animal husbandry. Taken together, the overall scientific synergy of ideas, reagents and expertise afforded by these multiple collaborations should enable this Program Project in Transfusion Medicine Research, to advance our understanding of the biology of blood and vascular cells, and to apply findings made toward treating blood diseases and enhancing the effectiveness of transfusion therapy.