MOLECULAR & CELLULAR MECHANISMS IN TRANSFUSION MEDICINE

描述（由申请人提供）： 这是计划项目资助HL-44612的第16-20年的修订后的竞争性更新申请，该计划项目资助HL-44612为输血医学领域重要的分子和细胞机制的协调，多学科研究提供支持-这门学科尽管对国家健康具有明显的重要性，但在培训和研究资源方面一直代表性不足。我们的申请反映了项目负责人之间十多年来持续的密切合作关系，他们仍然致力于围绕血液和血管细胞生物学的相关研究项目。 在第一个项目中，Peter和Debra纽曼提出了四个相互关联的目标，旨在进一步了解调节血小板活化和粘附的细胞表面受体和相关信号通路。在第二个项目中，Dick Aster建议继续研究暴露于阿昔单抗或配体模拟GPIIb/IIIa抑制剂的患者中导致急性血小板破坏的预先存在的“天然存在”抗体， 可能对其他免疫疾病有重要意义。由Cheryl Hillery领导的第三个项目旨在确定血液凝固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急性发作和伴随的慢性器官损伤的潜在疗法。由Bob蒙哥马利领导的第四个项目继续探索VWF生物合成的结构要求，为治疗重度血友病A患者的全新替代治疗方法奠定基础。 共享仪器核心将继续为DNA序列分析、肽合成、显微镜/数字图像分析、组织学、流式细胞术和细胞分选、BIAcore分析和单克隆抗体生产提供集中的仪器和专业知识。转基因/敲除小鼠核心将有助于载体设计、转基因小鼠生产、胚胎干细胞生长和转染、育种和畜牧业。总的来说，这些多重合作所提供的思想，试剂和专业知识的整体科学协同作用应该使输血医学研究项目能够促进我们对血液和血管细胞生物学的理解，并将研究结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.