Delineating factors to control differentiation of skin derived precursor cells

描述(申请人提供)：研究领域。本申请涉及广泛的挑战领域(14)：干细胞和特定挑战主题，14-AR-102：从人类皮肤和肌肉骨骼组织中发现多潜能和诱导多潜能干细胞的技术。成体干细胞是一种很有前途的资源，可用于开发基于细胞的疗法来治疗广泛的疾病。它们的应用不受伦理问题的阻碍，可以以患者量身定做的方式使用。皮肤的可获得性使被称为皮肤来源前体细胞(SKP)的多潜能成人干细胞群体成为一种特别有吸引力的细胞类型。限制这项技术发展的是缺乏从SKP中获得所需的具有生理活性的治疗细胞命运的有效方法。这个项目中提出的工作将描绘出小分子和蛋白质因子，它们可以指导SKP细胞的分化和重新编程到所需的谱系。长期目标包括鉴定促进有效地从人SKP细胞分化出髓鞘雪旺细胞和生理活性神经元的因素。移植的雪旺细胞被证明可以促进脊髓损伤后的功能恢复，并被认为在开发脱髓鞘疾病(如多发性硬化症)的治疗方法方面有希望。SKP来源的神经前体细胞可用于神经元替代疗法(如帕金森病的治疗)，刺激SKP细胞神经元诱导的因子可用于治疗周围神经疾病的内源性神经发生。将对大的类药物小分子文库(&gt；100万)和约4000个分泌蛋白的阵列集合进行无偏见的高通量筛选，以确定促进所需细胞命运推导的因素。在适当的情况下，将使用相关的活体小鼠模型和电生理学来验证有希望的导联的生理学效用。为了阐明在这些筛选中确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相结合来确定小分子靶标。这项工作将促进成体干细胞治疗应用的发展，并将导致识别调节其分化的生物学机制。此外，该项目的成功将提供先例，并为进一步努力确定控制干细胞命运的因素铺平道路。 与公共卫生相关：该项目的目标是识别有助于从人体皮肤中的干细胞高效衍生出治疗性细胞类型的分子。这些分子将推动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、多发性硬化症、帕金森病和各种周围神经疾病。

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.