Enhancement of Hematopietic Stem Cell Engraftment with CD+ Marrow Progenitors

CD 骨髓祖细胞增强造血干细胞植入

• 批准号: 8284391
• 负责人: Matthew J. Schuchert
• 金额: $ 12.49万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8284391
• 关键词: Allogenic; Bioluminescence; Bone Marrow; CD3 Antigens; CD8B1 gene; Cell Therapy; Cell physiology; Cells; Cellular Structures; Chest; Chimerism; Clinical; Data; Dendritic Cells; Development; Disease; Engraftment; Fluorescence Microscopy; Future; Green Fluorescent Proteins; Heart failure; Hematopoietic Neoplasms; Hematopoietic stem cells; Homologous Transplantation; Human; ITGAM gene; ITGAX gene; Image; Immunologic Deficiency Syndromes; In Vitro; Individual; Instruction; Knowledge; Label; Luciferases; Lymphoid; Marrow; Mediating; Mentored Clinical Scientist Development Award (K08); Mentorship; Modeling; Morphology; Mus; Myocardial Ischemia; Organ; Organ Transplantation; PTPRC gene; Patients; Pattern; Population; Principal Investigator; Regulatory T-Lymphocyte; Relative (related person); Research; Resources; Scientist; Stem cell transplant; Stem cells; Structure; Surgeon; T-Lymphocyte; Therapeutic; Time; Training Programs; Transplant Recipients; Transplantation; Transplantation Tolerance; Universities; Work; Xenograft procedure; cytokine; graft vs host disease; human stem cells; in vivo; innovation; insight; migration; progenitor; research study; skills; tissue regeneration; trafficking; treatment strategy

This mentored clinical scientist development award (K08) proposal describes the 5 year training program for Dr. Matthew J. Schuchert. This proposal builds upon the Candidate's strengths and prior research skills and takes advantage of the guidance and resources of the research scientists at the University of Pittsburgh. Through the mentorship of Dr. Angus Thomson, as well as a structured didactic component, the Candidate's ability to perform hypothesis-driven research will be advanced to a fully-independent surgeon scientist. The broad, long term objective of this project is to evaluate the mechanism(s) by which CD8+ marrow- derived subsets (CD8+/TCR-) enhance (facilitate) hematopoietic stem cell engraftment across allogeneic barriers In mice, resulting In the development of multllineage chlmerism and donor-specific transplantation tolerance without GVHD. Recent studies have demonstrated that cells resembling both plasmacytold pDCs (CD8+/CD11c+/B220+/CD11b-) and developing T cells (pTCs: CD8+/CD3+) exist within the FC population, which individually fail to achieve the complete facilitation effect. Therefore, we hypothesize that facilitation of allogeneic hematopoietic stem cell engraftment Is enhanced by the co-adminlstratlon of discrete CD8+ pDC and pTC progenitors working in concert to augment their tolerogenic effect. Specific Aim 1: Evaluate the functional contributions of individual CD8+/TCR- marrow-derived subsets. - Co-administration of pDC and pTC subsets will be assessed in vivo to examine facilitating potential. Specific Aim 2: Assess the cell trafficking and differentiation patterns of pDCs and pTCs. - EGFP and luclferase labelled pDC and pTC will be studied following allogeneic transplantation. Specific Aim 3: Evaluate potential mechanisms of FC function in vitro and in vivo. - Will evaluate potential mechanisms related to co-stimulation, cytokine polarity and Treg induction Specific Aim 4: Identification and characterization of facilitating subsets In human marrow. - Will characterize CD8+/TCR- subsets In human marrow, and assess facilitating potential in NOD-scid mice. Data from these studies will shed important Insights on cell-based therapies for tolerance induction. RELEVANCE (See instructions): A better understanding of pDC and pTC interactions will aid the development of innovative purified cell component therapeutic strategies for the treatment of hematopoietic malignancies, as well as for the support of human stem cells in a wide variety of clinical settings (hemaglobinopathies, immunodeficiencies, tissue regeneration, and ischemic heart failure). Such knowledge would afford new hope in thoracic organ transplant recipients and in patients suffering from a wide range of congenital and acquired hematologic disorders.

本指导临床科学家发展奖（K 08）提案描述了5年培训计划 马修·J·舒彻特医生的本建议书以候选人的优势和先前的研究技能为基础 并利用匹兹堡大学研究科学家的指导和资源。 通过安格斯汤姆森博士的指导，以及结构化的教学组成部分，候选人的 进行假设驱动研究的能力将提升为完全独立的外科医生科学家。 该项目的广泛、长期目标是评估CD 8+骨髓- 来源的亚群（CD 8 +/TCR-）增强（促进）造血干细胞在同种异体移植物中的植入。 在小鼠中的屏障，导致多谱系chimer症和供体特异性移植的发展 无GVHD的耐受性最近的研究表明，类似浆细胞的pDC (CD8+/CD 11 c +/B220+/CD 11b-）和发育中的T细胞（pTC：CD 8 +/CD 3+）存在于FC群体中， 其单独地不能实现完全的促进效果。因此，我们假设， 通过共施用离散的CD 8 + pDC来增强同种异体造血干细胞植入 和pTC祖细胞协同工作以增强它们的致耐受性作用。 具体目标1：评价单个CD 8 +/TCR-骨髓衍生亚群的功能贡献。 - 将在体内评估pDC和pTC子集的联合给药，以检查促进潜力。 具体目标2：评估pDC和pTC的细胞运输和分化模式。 - 将在异基因移植后研究EGFP和荧光素酶标记的pDC和pTC。 具体目标3：评价体外和体内FC功能的潜在机制。 - 将评价与共刺激、细胞因子极性和Treg诱导相关的潜在机制 具体目标4：人骨髓中促进亚群的鉴定和表征。 - 将表征人骨髓中的CD 8 +/TCR-亚群，并评估NOD-scid小鼠的促进潜力。 这些研究的数据将为基于细胞的耐受诱导疗法提供重要见解。 相关性（参见说明）： 更好地理解pDC和pTC相互作用将有助于开发创新的纯化细胞 治疗造血系统恶性肿瘤的组成治疗策略，以及支持 人类干细胞在各种临床环境（血红蛋白病，免疫缺陷，组织 再生和缺血性心力衰竭）。这些知识将为胸部器官移植提供新的希望 受体和患有广泛的先天性和获得性血液病的患者。