Specialized Center for Cell Based Therapy

描述(由申请人提供)： 干细胞可以被视为具有治疗潜力，无论是在外源性输送时，还是在内源性细胞对损伤做出反应时。这一提议的中心前提是，任何一种的成功治疗效果都取决于干细胞与复杂微环境的相互作用。这种微环境的调节成分作为一个综合系统发挥作用，提供了一个利基环境，调节干细胞的命运以响应生理刺激。然而，基于细胞的治疗的这一方面往往被忽视。我们之前已经证明，了解造血干细胞生态位的某些成分(成骨细胞及其对激素刺激的反应)可以导致在具有生理意义的背景下改善干细胞结果的策略(甲状旁腺激素刺激以改善骨髓移植)。在小鼠身上进行的这些研究提供了原理证据，证明了解和操纵干细胞的生态位可以产生与人类疾病相关的治疗结果。我们在这里的目的是沿着两条线扩展这种新颖的、基于细胞的治疗方法。首先，加深对造血干细胞利基成分的了解，并评估这些成分在体内的作用。其次，将从小鼠模型得出的这种理解转化为对患有血液病的人类的临床试验。因此，我们的计划由四个主要项目组成，两个基于实验室，两个基于临床。这些活动的主旨是：项目1：确定Wnt信号对成骨细胞生物学的影响，由Henry Kronenberg博士领导；项目2：确定骨髓利基的多种成分对干细胞功能的影响；项目3：通过嵌合动物研究、细胞操纵和临床试验团队将小鼠模型转换为人使用，由Gregor Adams博士领导的两项特定利基试验；项目4：使用Karen Ballen博士领导的临床试验财团在三项临床试验中测试对利基的操作，以此作为改善干细胞收获或干细胞植入的策略。它们将由三个核心支持。该提案的成功将为继续开发一种新的、基于利基的方法来治疗多种疾病提供理论基础。此外，它还将创建所需的基础设施，以迅速将此类疗法从小鼠模型转移到临床前评估，再到人类临床试验。

DESCRIPTION (provided by applicant): Stem cells can be viewed as having therapeutic potential either when delivered exogenously or when endogenous cells respond to injury. The central premise of this proposal is that successful therapeutic effect of either is dependent upon the interaction of the stem cells with a complex microenvironment. The regulatory components of this microenvironment function as an integrated system, providing a niche that modulates stem cell fate in response to physiologic stimuli. Yet this aspect of cell based therapy is often ignored. We have previously shown that understanding some components of the hematopoietic stem cell niche {the osteoblast and its response to hormonal stimulation) can lead to a strategy for improving stem cell outcomes in a physiologically meaningful context (parathyroid hormone stimulation to improve bone marrow transplantation). These studies in mice provided proof of principle that understanding and manipulating the stem cell niche can result in a therapeutic result relevant to human disease. Our intent here is to extend this novel, cell based approach to therapy development along two lines. First, to deepen understanding of the components of the hematopoietic stem cell niche and assess how these components function in vivo. Second, to convert this understanding derived from mouse models to clinical trials in humans with hematologic disease. Our program is therefore composed of four main projects, two laboratory based and two clinically based. The main thrust of these is: Project 1: define Wnt signaling effects on osteoblast biology led by Dr. Henry Kronenberg; Project 2: determine the impact of multiple constituents of the bone marrow niche on stem cell function led by Dr. David Scadden; Project 3: convert murine models to human use through chimeric animal studies, engagement of cell manipulation and clinical trial teams for two specific niche-related trials led by Dr. Gregor Adams; Project 4: test manipulation of the niche as a strategy to improve stem cell harvesting or stem cell engraftment in three clinical trials using a clinical trial consortium led by Dr. Karen Ballen. These will be supported by three cores. Success of the proposal will provide rationale for continued development of a novel, niche-based approach to cell therapies for multiple disease entities. Further, it will create infrastructure needed to rapidly move such therapies from mouse model to pre-clinical assessment to human clinical trial.