Ex Vivo Expansion of Cord Blood Progenitor Cells

脐带血祖细胞的离体扩增

• 批准号: 7436309
• 负责人: Colleen Delaney
• 金额: $ 12.83万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7436309
• 关键词: Adult; Blood Cells; CD34 gene; CD34+ precursor; Cell Count; Cell Density; Cell Transplantation; Cells; Child; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Development; Dose; Effectiveness; Engineering; Engraftment; Enrollment; Foundations; Generations; Goals; Grant; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Immunodeficient Mouse; Individual; Infection; Infusion procedures; Interleukin-3; Investigation; Laboratories; Ligands; Lymphoid; Mediating; Mentors; Methodology; Methods; Myelogenous; Numbers; Outcome; Patients; Phase I Clinical Trials; Population; Preparation; Relative (related person); Research Training; SCID Mice; Safety; Secondary to; Signal Transduction; Source; Stem cells; System; Time; Training; Training Programs; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Universities; Washington; base; clinically relevant; cytokine; hematopoietic repopulating cell; improved; mortality; notch protein; novel; pre-clinical; preclinical study; progenitor; programs; reconstitution; research clinical testing; self-renewal; success

DESCRIPTION (provided by applicant): The candidate's immediate goal is to acquire critical scientific and clinical training to enable her to pursue independent investigation with the long-term goal of improving the outcome for recipients of hematopoietic cell transplantation (HCT) with umbilical cord blood (UCB). UCB is used as an alternative source of stem cells for HCT only when the patient cannot identify an otherwise suitable related or unrelated donor. This is secondary to poor outcomes following umbilical cord blood transplantation (UCBT), especially in adults and larger children, due to inadequate cell numbers in the graft leading to delayed engraftment that is often associated with lethal infection. The proposed grant will integrate two complimentary approaches: 1. the preclinical development of a novel ex vivo stem cell expansion system using Delta1, a Notch ligand that is a known regulator of cell fate determination, and 2. the clinical evaluation of outcomes of UCBT using ex vivo expanded cells. In preclinical studies, we hypothesize that UCB progenitor cells cultured on Notch ligand will result in self-renewal of repopulating cells, thereby increasing the number of these cells available for transplantation. Our laboratory has developed a novel expansion method for enhancing the repopulating capacity of hematopoietic progenitor cells, and in preliminary studies with cord blood progenitor cells, culture with engineered Notch ligand increased the number of CD34+ precursors and substantially enhanced their repopulating ability in immunodeficient mice. We further hypothesize that the effectiveness of this approach will depend on a number of critical variables, including dose of Notch ligand and signaling, choice of cytokines, starting cell population (CD34+ vs CD34+38-) and cell density. In clinical studies, the candidate will assess the outcome of UCBT using cells expanded by the above optimized methodology. Additionally, a rigorous didactic and mentoring program in clinical trial design will provide the candidate the foundation to implement and supervise clinical trials of conventional UCBT augmented with ex vivo expanded cells.

描述（由申请人提供）： 候选人的近期目标是获得批判性的科学和临床培训，以使她能够进行独立的调查，其长期目标是通过脐带血（UCB）改善造血细胞移植（HCT）的结果。仅当患者无法识别出其他合适的相关或无关的供体时，UCB才能用作HCT干细胞的替代来源。这是脐带血移植（UCBT）之后的较差的结果，尤其是在成年人和较大的儿童中，由于移植物中的细胞数量不足，导致延迟植入植入，这通常与致死感染有关。拟议的赠款将整合两种免费方法：1。使用Delta1（一种已知的细胞命运确定调节剂）和2。使用EX VIVO Expanded细胞对UCBT结果的临床评估。在临床前研究中，我们假设在Notch配体上培养的UCB祖细胞会导致重新培养细胞的自我更新，从而增加可用于移植的这些细胞的数量。我们的实验室开发了一种新型的扩展方法，可增强造血祖细胞的重塑能力，在使用脐带血祖细胞的初步研究中，具有工程凹配体的培养培养物增加了CD34+前体的数量，并大大提高了其在免疫缺乏小鼠中的养殖能力。我们进一步假设，这种方法的有效性将取决于许多关键变量，包括Notch配体和信号传导，选择细胞因子的选择，启动细胞群（CD34+ VS CD34+ 38-）和细胞密度。在临床研究中，候选人将使用上述优化方法扩展的细胞来评估UCBT的结果。此外，临床试验设计中的一项严格的教学和指导计划将为候选人提供基础，以实施和监督传统UCBT的临床试验，并通过体内扩展的细胞增强。