Delineating factors to control differentiation of skin derived precursor cells

描述（由申请人提供）：研究领域。本申请涉及广泛的挑战领域（14）：干细胞和特定的挑战主题，14-AR-102：从人类皮肤和肌肉骨骼组织中发现多能和诱导多能干细胞的技术。成体干细胞代表了用于开发基于细胞的疗法以治疗广泛疾病的有前途的资源。它们的应用不会受到伦理问题的阻碍，并且可以以患者定制的方式使用。皮肤的可及性使得称为皮肤衍生前体（SKP）细胞的多能成体干细胞群体成为特别有吸引力的细胞类型。限制该技术发展的是缺乏从SKPs获得所需生理活性治疗细胞命运的有效方法。该项目中提出的工作将描述小分子和蛋白质因子，这些因子可以指导SKP细胞分化和重编程为所需的谱系。长期目标包括鉴定促进从人SKP细胞有效衍生髓鞘化雪旺细胞和生理活性神经元的因子。移植的许旺细胞已被证明可促进脊髓损伤后的功能恢复，并被认为有望开发脱髓鞘疾病（例如多发性硬化症）的治疗方法。来源于SKP的神经元祖细胞可用于神经元替代疗法（例如用于治疗帕金森病），并且刺激SKP细胞中神经元诱导的因子可在治疗上用于刺激内源性神经发生以治疗周围神经病。将对药物样小分子的大文库（> 1百万）和约4000种分泌蛋白的阵列集合进行无偏高通量筛选，以鉴定促进所需细胞命运的衍生的因子。将使用相关的体内小鼠模型和电生理学（如适用）确认有前景的电极导线的生理效用。为了阐明在这些筛选中鉴定的因子的生物学机制，将使用基于基因组和生物化学亲和力的方法的组合来确定小分子命中的靶标。这项工作将促进成体干细胞治疗应用的发展，并将导致介导其分化的生物学机制的鉴定。此外，该项目的成功将为进一步努力确定控制干细胞命运的因素提供先例并铺平道路。 公共卫生相关性：该项目的目标是确定有助于从人类皮肤中的干细胞有效衍生治疗细胞类型的分子。这些分子将促进基于细胞的疗法的发展，以治疗一系列与神经系统相关的疾病。潜在的应用将是开发细胞移植策略来治疗脊髓损伤、多发性硬化、帕金森病和各种周围神经病变。

DESCRIPTION (provided by applicant): Research Area. This application addresses broad Challenge Area (14): Stem Cells and specific Challenge Topic, 14-AR-102: Discovery Technologies for Multipotent and Induced Pluripotent Stem Cells from Human Skin and Musculoskeletal Tissues. Adult stem cells represent a promising resource for the development of cell based therapies to treat a broad range of diseases. Their application is not hampered by ethical concerns and they can be used in a patient tailored manner. The accessibility of skin makes a multipotent adult stem cell population known as skin derived precursor (SKP) cells a particularly attractive cell type. Limiting the development of this technology is the lack of efficient methods to derive desired physiologically active therapeutic cell fates from SKPs. The work proposed in this project will delineate small molecule and protein factors that can direct the differentiation and reprogramming of SKP cells to a desired lineage. Long term objectives include the identification of factors that facilitate the efficient derivation of myelinating Schwann cells and physiologically active neurons from human SKP cells. Transplanted Schwann cells have been shown to promote functional recovery following spinal cord injury and are believed to hold promise in the development of treatments for demyelination diseases (e.g. multiple sclerosis). Neuron progenitor cells derived from SKPs could be used in neuron replacement therapies (e.g. for the treatment of Parkinson's disease) and factors that stimulate neuron induction in SKP cells could be used therapeutically to stimulate endogenous neurogenesis for the treatment of peripheral neuropathies. Unbiased high throughput screens of large libraries (> 1 million) of drug-like small molecules and arrayed collections of ~4000 secreted proteins will be performed to identify factors that facilitate the derivation of desired cell fates. The physiological utility of promising leads will be validated using relevant in vivo mouse models and electrophysiology, where appropriate. To elucidate the biological mechanisms of factors identified in these screens, targets of small molecule hits will be determined using a combination of genomic and biochemical affinity based approaches. This work will facilitate the development of therapeutic applications for adult stem cells and will lead to the identification of biological mechanisms that mediate their differentiation. In addition, success in this project will serve to provide precedence and pave the way for additional efforts to identify factors that control stem cell fate. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify molecules that facilitate the efficient derivation of therapeutic cell types from stem cells that reside in human skin. These molecules will advance the development of cell based therapies to treat a range of diseases related to the nervous system. Potential applications will be the development of cell transplantation strategies to treat spinal cord injury, multiple sclerosis, Parkinson's disease and various peripheral neuropathies.