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Multifaceted Interventions to Amplify HSC Engraftment

多方面干预措施以扩大 HSC 植入

基本信息

批准号：
7597009
负责人：
CHRISTIE M Orschell
金额：
$ 35.91万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7597009
关键词：
Address Adult Bone Marrow Bone Marrow Cells Cell Transplants Cell physiology Cells Characteristics Complex Data Disease Dose Engraftment Gene-Modified Goals Hand Hematopoiesis Hematopoietic Hematopoietic Neoplasms Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Home environment Homing Individual Integration Host Factors Intervention Laboratories Lead Methods Modality Modeling Mus Non-Malignant One-Step dentin bonding system Patients Pattern Physiological Population Probability Process Processed Genes Protocols documentation Publishing Radiation Relative (related person)Research Personnel Resolution Scheme Signal Transduction Source Stem cell transplant Stem cells Stromal Cells Techniques Testing Therapeutic Time Toxic effect Transplantation Treatment Protocols Umbilical Cord Blood Work base chemotherapy clinically relevant conditioning expectation experience gene correction gene therapy improved in vivo irradiation older patient programs protocol development reconstitution response self-renewal stem cell biology success

项目摘要

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。这种竞争在清髓调节的HSC毒性作用后可以忽略不计，而非清髓调节后大量宿主HSC的残留限制了非消融HSC移植（SCT）的成功。据报道，增加移植的HSC数量可以抵消宿主HSC的大量储备，但对于许多患者或某些类型的SCT来说，供体HSC并不是普遍可用的。该提议的假设是，有限数量的HSC的整体移植潜力可以通过在SCT过程中几个不同方面的干预来增加，包括移植物的调节、宿主的调节方案和利用宿主的内在参数。这些干预措施旨在增加造血潜能、归巢、移植造血干细胞的存活和增殖。将实现以下三个具体目标：