Molecular Mechanisms of Blood Cell Transfusion

血细胞输注的分子机制

• 批准号: 9294145
• 负责人: Leslie Eric Silberstein
• 金额: $ 199.49万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294145
• 关键词: Animal Husbandry; Animals; Antibodies; Bacterial Infections; Blood Cells; Blood Platelets; Blood Transfusion; Bone Marrow; Bone Marrow Transplantation; Breeding; CD34 gene; CXCL12 gene; Cell Therapy; Cells; Chromatin; Clinical; Clinical Sciences; Collaborations; Complex; Cytometry; Engraftment; Ensure; Enzymes; Epigenetic Process; Erythrocytes; Event; Faculty; Flow Cytometry; Frequencies; Functional disorder; Glues; Goals; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Image; Infection; Inflammation; Inflammatory; Investigation; Joints; Knockout Mice; Laser Scanning Cytometry; Link; Marrow; Medical; Medicine; Molecular; Mycoses; Natural regeneration; Outcome; Pancytopenia; Pathway interactions; Patients; Performance; Platelet Transfusion; Principal Investigator; Production; Productivity; Property; Public Health; Reagent; Recording of previous events; Recovery; Repression; Research; Research Project Grants; Resources; Role; Signal Transduction; Specialist; Specific qualifier value; Stem cell transplant; Stress; Stromal Cells; Sum; Supporting Cell; Technology; Therapeutic Uses; Tissues; Transcriptional Regulation; Transfusion; Transgenic Mice; Translating; Transplantation; United States National Institutes of Health; Wages; Yeasts; Zinc Fingers; base; blood product; clinical practice; cohesion; combat; cost effective; design; experience; granulocyte; hematopoietic cell transplantation; improved; inflammatory modulation; innovation; inositol heptakisphosphate; insight; medical schools; multidisciplinary; novel therapeutic intervention; operation; phosphatidylinositol 3,4,5-triphosphate; programs; therapeutic evaluation; therapeutic target; trait; transcription factor; virtual

 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)

 描述（由申请人提供）：这是 P01 HL095489 的竞争性更新申请，为题为“血细胞输血的分子机制”的协调、多学科项目提供支持。该研究项目的长期主题目标是。为接受干细胞移植的患者开发更有效的输血医学支持，因为围移植期的患者需要大量的输血支持（包括红细胞、血小板和粒细胞）。移植相关的骨髓 (BM) 功能障碍状态 在本申请中，我们研究骨髓功能障碍部分是由造血基质生态位受损引起的（项目 1）；植入受到可移植造血干细胞/祖细胞数量的限制（ HSPC）（项目 2）；并且可以优化粒细胞输注治疗移植周围（细菌和酵母菌）感染的功效（项目 3）。研究人员、项目负责人和核心负责人都是哈佛医学院输血医学联合项目 (JPTM) 项目 1 的教员，Leslie Silberstein 博士将阐明表达 CXCL12 的基质微环境细胞在炎症应激期间造血过程中的动态作用。这项研究将为骨髓功能障碍状态下的造血再生带来新的治疗方法，这需要大量的血液制品支持。项目2，柴力博士将尝试了解造血干细胞。该项目将重点关注 SALL4，一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。项目3，罗红波博士将研究粒细胞输注中的细胞信号传导，最终目标是识别可以改善粒细胞的细胞和分子事件。他们试图通过靶向 InsP6K1（一种负责合成 InsP7 的酶，InsP7 是一种负调节 PtdIns(3,4,5)P3 的胞质分子）来增强细胞内 PtdIns(3,4,5)P3 信号传导来实现这一目标。三个支持核心是：管理核心、动物核心和细胞计数核心。管理核心将监督和协调日常科学工作。细胞计数核心将为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细胞和亚细胞标准的成像和定量分析提供具有成本效益的集中资源。使用激光扫描细胞术（LaSC）技术在组织内进行实验动物核心将有助于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，该计划将产生可直接转化为优化的重要见解和信息。输血医学中心为围移植期间需要输血的患者提供支持。 （摘要完） 项目 1：骨髓中表达 CXCL12 的微环境细胞的炎症调节 （西尔伯斯坦，莱斯利·埃里克）