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时，无论是外源性交付或内源性细胞响应损伤。这一建议的中心前提是，成功的治疗效果取决于干细胞与复杂微环境的相互作用。该微环境的调节组分作为一个集成系统起作用，提供调节干细胞命运以响应生理刺激的小生境。然而，基于细胞的治疗的这一方面往往被忽视。我们以前已经表明，理解造血干细胞生态位的某些组成部分（成骨细胞及其对激素刺激的反应）可以导致在生理上有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）。这些在小鼠中的研究提供了原理证明，即理解和操纵干细胞生态位可以产生与人类疾病相关的治疗结果。我们的目的是沿着沿着两条路线将这种新颖的、基于细胞的方法扩展到治疗开发。首先，加深对造血干细胞生态位组成部分的理解，并评估这些组成部分如何在体内发挥作用。第二，将这种从小鼠模型中获得的理解转化为人类血液病的临床试验。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。这些项目的主要重点是：项目1：由亨利Kronenberg博士领导的定义Wnt信号传导对成骨细胞生物学的影响;项目2：由大卫斯卡登博士领导的确定骨髓生态位的多种成分对干细胞功能的影响;项目3：通过嵌合动物研究将鼠模型转化为人类使用，由Gregor亚当斯博士领导的两项特定利基相关试验的细胞操作和临床试验团队参与;项目4：在三项临床试验中，使用由Karen Ballen博士领导的临床试验联盟，测试操作利基作为改善干细胞收获或干细胞植入的策略。这些将由三个核心提供支持。 该提案的成功将为继续开发用于多种疾病实体的新型基于利基的细胞疗法提供理论基础。此外，它还将创建所需的基础设施，以快速将此类疗法从小鼠模型转移到临床前评估和人体临床试验。

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.