Investigating regulators controlling differentiation potential of ES cells

 描述(由申请人提供)：自我更新和多能性是胚胎干细胞(来自发育中的胚胎)和诱导多能干细胞(来自分化的体细胞)中常见的干细胞的特征。这些细胞在体外可以长时间自我更新并保持分化。 潜在的(多能性)，产生所有可能的细胞类型的发育中的生物体。由于这些特殊的特性，ES和iPS细胞被广泛研究，以了解早期发育的分子基础，并在药物发现和建立人类疾病模型方面发挥有用的工具作用。自从转录因子Oct4、Sox2和Nanog在ES细胞中被确定为在自我更新过程中发挥主调节作用以来，高通量技术的进步导致了更多主调节因子的发现。这些发现使我们能够更好地了解干细胞自我更新的调控机制。另一方面，我们对保持干细胞分化潜力的调控机制的理解受到很大限制，这种机制还没有得到系统的研究。显然，对自我更新和多能性的全面了解对于在未来的治疗应用中充分利用多能性干细胞的潜力至关重要。这项研究的目的是为了更好地了解调控ES细胞分化潜能的调控机制。我们的主要问题是：1)维持和控制多能干细胞分化潜能的转录因子是什么？2)它们如何影响早期谱系指定的方向？3)本质是什么？ 这些网络如何与先前已知的自我更新网络交织在一起？我们将通过应用基于签名的筛选方法结合各种系统生物学工具来系统地解决这些问题。该项目的成功完成不仅将使我们能够从功能上表征控制干细胞分化潜力的新型调控因子，而且还将全面展示管理多能干细胞标志的调控机制。此外，这一提议的结果将为操纵干细胞以控制细胞命运走向理想的谱系提供基础，并有助于基于干细胞的治疗的进展。

 DESCRIPTION (provided by applicant): Self-renewal and pluripotency are defining characteristics of stem cells common in both embryonic stem (ES) cells (derived from developing embryos) and induced pluripotent stem (iPS) cells (derived from differentiated somatic cells). These cells can self-renew for a prolonged time in vitro and retain differentiation potential (pluripotency) to give rise to all possible cell types of developing organisms. Due to such exceptional characteristics, ES and iPS cells have been studied extensively for understanding the molecular basis of early development, and serve as useful instruments in drug discovery and establishing human disease models. Since transcription factors, Oct4, Sox2, and Nanog have been identified in ES cells as playing master regulatory roles in self-renewal processes, advances in high-throughput technologies have led to the discovery of additional cofactors of master regulators. These discoveries have allowed us to better understand the regulatory mechanisms of stem cell self-renewal. On the other hand, our understanding of the regulatory mechanisms that retain the differentiation potential of stem cells is significantly limied and such mechanisms have not yet been systematically examined. Obviously, complete understanding of both self-renewal and pluripotency would be crucial in harnessing the full potential of pluripotent stem cells in future therapeutic applications. The objective of the proposed research is to better understand the regulatory mechanisms governing the differentiation potential of ES cells. Our primary questions are 1) What are the transcription factors involved in maintaining and controlling the differentiation potential of pluripotent stem cells? 2) How do they influence the direction of early lineage specification? 3) What is the nature of the regulatory networks they form, and how do these networks intertwine with the previously known self-renewal network? We will address these questions systematically by applying a signature based screening method in combination with various systems biology tools. Successful completion of this project will not only allow us to functionally characterize novel regulators controlling the differentiation potential of stem cells, but also illustrate the full viw of regulatory mechanisms governing the hallmarks of pluripotent stem cells. Furthermore, outcomes of this proposal will provide a foundation for manipulation of stem cells to control cell fates towards desired lineages, and contribute to the advances in stem cell based cell therapies.