Ex Vivo Expansion of Cord Blood Progenitor Cells

描述（由申请人提供）： 候选人的近期目标是获得关键的科学和临床培训，使她能够进行独立的研究，长期目标是改善造血细胞移植（HCT）与脐带血（UCB）的结果。只有当患者无法确定合适的相关或不相关供体时，UCB才被用作HCT的干细胞替代来源。这是继发于脐带血移植（UCBT）后的不良结局，特别是在成人和较大的儿童中，由于移植物中细胞数量不足导致植入延迟，这通常与致命感染有关。拟议的赠款将结合两个互补的方法：1。使用Delta 1的新型离体干细胞扩增系统的临床前开发，Delta 1是一种Notch配体，其是已知的细胞命运决定调节剂，以及2.使用体外扩增细胞的UCBT的结果的临床评价。在临床前研究中，我们假设在Notch配体上培养的UCB祖细胞将导致再生细胞的自我更新，从而增加可用于移植的这些细胞的数量。我们的实验室已经开发出一种新的扩增方法，用于增强造血祖细胞的重建能力，并在脐带血祖细胞的初步研究中，与工程Notch配体的培养物增加了CD 34+前体的数量，并大大增强了它们在免疫缺陷小鼠中的重建能力。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配体和信号传导的剂量、细胞因子的选择、起始细胞群体（CD 34 + vs CD 34 +38-）和细胞密度。在临床研究中，候选人将使用通过上述优化方法扩增的细胞评估UCBT的结果。此外，临床试验设计中严格的教学和指导计划将为候选人提供实施和监督体外扩增细胞增强的常规UCBT临床试验的基础。

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.