Enhancement of Hematopietic Stem Cell Engraftment with CD+ Marrow Progenitors

描述（由申请人提供）：本指导临床科学家发展奖（K 08）提案描述了Matthew J. Schuchert博士的5年培训计划。该提案基于候选人的优势和先前的研究技能，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，以及一个结构化的教学组成部分，候选人的能力，执行假设驱动的研究将提前到一个完全独立的外科医生科学家。本项目的广泛、长期目标是评估CD 8+骨髓衍生亚群（CD 8 +/TCR-）增强（促进）小鼠中造血干细胞跨越同种异体屏障植入的机制，从而导致多谱系嵌合体和供体特异性移植耐受性的发展而无GVHD。最近的研究表明，类似浆细胞的pDC（CD 8 +/CD 8 + pDC和pTC祖细胞）的细胞协同工作以增强其致耐受性作用。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子集的共同施用以检查促进潜力。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。- 将评估与共刺激、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（见说明书）：患有各种先天性和后天性血液病的患者。 (End摘要）

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)