Molecular Mechanisms of Blood Cell Transfusion

 描述（由申请人提供）：这是P01 HL 095489的竞争性续展申请，为一个名为“血细胞输注的分子机制”的协调、多学科计划项目提供支持。该研究计划的长期主题目标是为接受干细胞移植的患者开发更有效和更有效的输血医学支持。由于移植相关的骨髓（BM）功能障碍状态，围移植期患者需要大量输血支持（包括红细胞、血小板和粒细胞）。在本申请中，我们假设骨髓功能障碍部分是由受损的造血基质生态位引起的（项目1）;植入受可移植造血干/祖细胞（HSPC）数量的限制（项目2）;粒细胞输注治疗移植围手术期（细菌和酵母菌）感染的疗效可以优化（项目3）。主要研究者、项目负责人和核心领导人都是哈佛医学院输血医学联合项目（JPTM）的教员。Leslie Silberstein博士将阐明炎症应激期间表达CXCL 12的基质小生境细胞在造血中的动态作用。这项研究将为骨髓功能障碍状态下的造血再生提供新的治疗方法，这需要大量的血液制品支持。项目二，柴立博士将通过研究转录因子和表观遗传调节因子（染色质修饰因子）之间的相互作用，试图了解造血干/祖细胞的特性。该项目将重点关注SALL 4，这是一种与激活和抑制表观遗传复合物相互作用的锌指转录因子。假设新鉴定的SALL 4活化途径对CD 34 + HSPC扩增很重要。项目3，罗洪波博士将研究粒细胞输注中的细胞信号传导。最终目标是确定可以改善输血后粒细胞性能的细胞和分子事件。他们试图通过靶向InsP 6 K1来提高细胞内PtdIns（3，4，5）P3信号传导来实现这一目标，InsP 6 K1是一种负责合成InsP 7的酶，InsP 7是一种负调节PtdIns（3，4，5）P3信号传导的细胞溶质分子。三个支持核心是：管理核心、动物核心和细胞计数核心。行政核心将监督和协调该计划的日常科学和财政运作。Cytometry Core将为使用基于抗体的细胞预富集、基于流式细胞术的细胞分析和纯化以及使用激光扫描细胞术（LaSC）技术对组织内的细胞和亚细胞标准进行成像和定量分析提供具有成本效益的集中资源。实验动物核心将协助转基因和基因敲除小鼠的生产，多性状育种和畜牧业。总的来说，该计划将产生重要的见解和信息，这些见解和信息将直接转化为优化输血医学支持，以支持需要在围移植环境中输血的患者。 (End摘要） 项目1：骨髓中表达CXCL 12的小生境细胞的炎症调节 （西尔伯斯坦，莱斯利埃里克）

 DESCRIPTION (provided by applicant): This is a competitive renewal application of P01 HL095489, which provides support for a coordinated, multi- disciplinary program project entitled "Molecular mechanisms of blood cell transfusion". The long-term thematic objective of this research program is to develop more efficient and effective Transfusion Medicine support for patients undergoing stem cell transplantation. Patients in the peri-transplant period require significant transfusion support (including red blood cells, platelets and granulocytes) because of the transplant-related bone marrow (BM) dysfunction state. In this application we hypothesize that bone marrow dysfunction is caused in part by a compromised hematopoietic stromal niche (project 1); that engraftment is limited by the quantity of transplantable hematopoietic stem/progenitor cells (HSPC) (project 2); and that the efficacy of granulocyte transfusions towards the treatment of peri-transplant (bacterial and yeast) infections can be optimized (project 3). The principal investigators, project leaders, and core leaders are all faculty of the Joint Program in Transfusion Medicine (JPTM) at Harvard Medical School. Project 1, Dr. Leslie Silberstein will elucidate the dynamic role of CXCL12 expressing stromal niche cells in hematopoiesis during inflammatory stress. This study will lead to new therapeutic approaches for hematopoietic regeneration in bone marrow dysfunction states, which require significant blood product support. Project 2, Dr. Li Chai will try to understand hematopoietic stem progenitor cell properties by investigating the interaction between transcription factors and epigenetic modulators (chromatin modifiers). This project will focus on SALL4, a zinc-finger transcription factor that interacts with both activation and repression epigenetic complexes. The hypothesis is that a newly identified SALL4 activation pathway is important for CD34+ HSPC expansion. Project 3, Dr. Hongbo Luo will study cell signaling in granulocyte transfusion. The ultimate goal is to identify cellular and molecular events that can improve granulocyte performance after transfusion. They try to achieve this by elevating intracellular PtdIns(3,4,5)P3 signaling via targeting InsP6K1, an enzyme responsible for the synthesis of InsP7, a cytosolic molecule that negatively regulates PtdIns(3,4,5)P3 signaling. The three supporting cores are: Administrative Core, Animal Core, and a Cytometry Core. The Administrative Core will oversee and coordinate the day-to- day scientific and fiscal operation of the Program. The Cytometry Core will provide a cost-effective, centralized resource for the use of antibody based cellular pre-enrichment, flow cytometry based cell analysis and purification, as well as imaging and quantitative analysis of cellular and subcellular criteria within tissues using laser scanning cytometry (LaSC) technology. The Experimental Animal Core will assist with transgenic and knockout mouse production, multi-trait breeding, and animal husbandry. Collectively, this program will yield significant insight and information that will directly translate into optimizatin of Transfusion Medicine support of patients requiring transfusion in the peri-transplant setting. (End of Abstract) PROJECT 1: INFLAMMATORY MODULATION OF CXCL12 EXPRESSING NICHE CELLS IN BONE MARROW (SILBERSTEIN, LESLIE ERIC)