Enhancement of Hematopietic Stem Cell Engraftment with CD+ Marrow Progenitors

描述（由申请人提供）：这份指导临床科学家发展奖（K08）提案描述了Matthew J. Schuchert博士的5年培训计划。该提案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，以及结构化的教学成分，候选人进行假设驱动研究的能力将提升到一个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CD8+骨髓衍生亚群（CD8+/TCR-）增强（促进）造血干细胞在小鼠体内跨越异体屏障的机制，从而产生多谱系嵌合和无GVHD的供体特异性移植耐受。最近的研究表明，类似于浆细胞指示的pDC （CD8+/CD8+ pDC和pTC祖细胞）的细胞协同作用以增强其耐受性。具体目标1：评估单个CD8+/TCR-骨髓衍生亚群的功能贡献。-将在体内评估pDC和pTC亚群的联合给药，以检查促进潜力。具体目标2：评估pDCs和ptc的细胞运输和分化模式。- EGFP和荧光素酶标记的pDC和pTC将在异体移植后进行研究。具体目标3：评估体外和体内FC功能的潜在机制。-将评估与共刺激、细胞因子极性和Treg诱导相关的潜在机制特异性目标4：鉴定和表征人骨髓中促进亚群。-将表征人骨髓中的CD8+/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性诱导疗法提供重要的见解。相关性（见说明书）：患有多种先天性和后天性血液病的患者。（摘要结束）

DESCRIPTION (provided by applicant): 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 chimerism and donor-specific transplantation tolerance without GVHD. Recent studies have demonstrated that cells resembling both plasmacytold pDCs (CD8+/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 labeled 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 betents suffering from a wide range of congenital and acquired hematologic disorders. (End of Abstract)