Multifaceted Interventions to Amplify HSC Engraftment

多方面干预措施以扩大 HSC 植入

• 批准号: 6925588
• 负责人: CHRISTIE M Orschell
• 金额: $ 37.88万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6925588
• 关键词: apoptosis; biological models; cell cycle; cell proliferation; clinical research; flow cytometry; hematopoietic stem cells; hematopoietic tissue transplantation; human subject; laboratory mouse; model design /development; phenotype; radiation dosage; radiobiology; secretory protein; stem cell transplantation; stromal cells; tissue donors

DESCRIPTION (provided by applicant): The degree of donor cell engraftment following hematopoietic stem cell (HSC) transplantation is determined by the level of host stem cell competition. This competition is negligible after HSC-toxic effects of myeloablative conditioning, whereas the large number of host HSC remaining after non-myeloablative conditioning limits the success of non-ablative HSC transplantation (SCT). Increasing the number of transplanted HSC reportedly counteracts large reserves of host HSC, but excess donor HSC are not universally available for many patients or in certain types of SCT. The hypothesis of this proposal is that the overall engraftment potential of limited numbers of HSC can be increased by interventions at several different fronts in the SCT process, including modulation of the graft, conditioning regimens of the host, and exploitation of intrinsic host parameters. These interventions are aimed to increase hematopoietic potential, homing, survival and proliferation of transplanted HSC. The following three specific aims will be pursued: 1. Investigate how the graft itself can be manipulated prior to transplantation to increase its engraftment potential. 2. Examine how different host conditioning regimens impact homing, survival, proliferation, and subsequent engraftment potential of transplanted hematopoietic stem cells. 3. Identify and exploit intrinsic host parameters to increase overall engraftment potential of transplanted hematopoietic stem cells. A multi-factorial scheme utilizing sophisticated techniques and in vivo function to identify HSC will be employed to investigate these interventions using a murine SCT model. Our long-term goal is to understand the complex mechanisms by which transplanted HSC home to, survive within, and commence proliferation and self-renewal processes in host BM, and to manipulate these processes to increase engraftment potential of limited numbers of donor HSC. The significance of this work is the likelihood that it will provide new protocols in SCT for the ultimate benefit of patients receiving ex vivo manipulated grafts such as those processed for gene therapy purposes, or patients ineligible for myeloablative conditioning regimens or other protocols where the low ratio of donor to host HSC will likely lead to low or failed engraftment.

描述（由申请人提供）：造血干细胞（HSC）移植后供体细胞植入的程度取决于宿主干细胞竞争的水平。在骨髓性调节的HSC毒性作用后，这项竞争是可忽略的，而在非毛线不公动条件后，大量的宿主HSC却限制了非易生HSC移植（SCT）的成功。据报道，增加移植的HSC数量可以抵消大量宿主HSC的储量，但是多余的供体HSC并不能普遍使用许多患者或某些类型的SCT。该提议的假设是，在SCT过程中的几个不同方面的干预措施，包括移植物的调节，宿主的调节方案以及对内在宿主参数的利用，可以通过在几个不同方面进行干预来增加HSC数量有限的总体植入潜力。这些干预措施旨在增加移植HSC的造血潜力，归巢，存活和增殖。以下三个具体目标将被追求： 1。研究移植前如何操纵移植物本身以提高其植入潜力。 2。检查不同的宿主调节方案如何影响归巢，生存，增殖以及随后的移植造血干细胞的植入潜力。 3。识别和利用固有的宿主参数，以增加移植造血干细胞的整体植入潜力。 利用复杂技术和体内功能识别HSC的多因素方案将使用鼠SCT模型来研究这些干预措施。我们的长期目标是了解将HSC移植，在宿主BM中移植，生存并开始扩散和自我更新过程的复杂机制，并操纵这些过程以增加供体数量有限的HSC的植入潜力。这项工作的意义在于，它可能会在SCT中提供新方案，以便接受过体内操纵的移植物（例如用于基因治疗目的的患者），或者有资格获得骨髓性调理方案或其他方案的患者，而捐助者比率低比率可能会导致HSC低或失败。