Identifying chemical agents that affect human embryonic stem cells in vitro and determining their molecular targets.

细胞使用复杂的生化机制来控制它们的行为，而干扰这些过程的工具使科学家能够研究细胞是如何工作的。这有助于更好地理解生物学，在某些情况下，可以为疾病提供新的诊断和治疗方法。干细胞，特别是胚胎干细胞是近年来科学研究的热点。干细胞的定义是自我更新的能力——一个分裂过程，产生两个与原细胞完全相同的新细胞。这对于在胚胎发育期间和在细胞经常丢失的成人系统中产生适当数量的细胞是重要的。干细胞也可以分化，这是一个变化的过程，导致形成一种特征与原始细胞不同的细胞类型。这产生了形成和维持身体器官和组织所需的细胞多样性（如肌肉、神经、肝脏）。另一种可能是干细胞或其衍生物经历程序性细胞死亡——一种被称为细胞凋亡的过程——这可以防止细胞的过度产生，并可以消除那些遭受严重损害的细胞。维持自我更新、分化和凋亡之间的正确平衡是多细胞生物的基本特征。在最基本的层面上，这种平衡是由基因表达控制的。选择性地使用细胞DNA的某些部分，而不是全部部分，会导致产生的特定蛋白质的相对数量发生变化。这反过来又影响细胞内的生化反应并改变它们的行为。已经开发了许多方法，可以人工控制基因表达，允许检查单个基因的功能。然而，这些技术是耗时的，在某些情况下，不可靠或其效果短期。避免这些问题的方法将有助于科学家更有效地开展研究。一种可能性是以化学制剂的形式存在的。由于化学制剂在形状、大小和组成上的巨大多样性，它们不仅限于影响基因和基因表达。只要有合适的分子结构，理论上任何细胞成分都可以被靶向并改变其功能。此外，化学物质可以简单地添加到生物系统中，而不需要任何复杂的制备，并且可以通过改变剂量来控制效果的大小。找到能够对特定生物目标产生作用的化学物质是困难的。从头开始设计改变细胞特定成分功能的化学物质的方法是不可靠的。相反，最成功的方法包括测试大量不同的、现成的化学物质，以识别那些在生物系统中引起行为变化的化学物质；这可以是一只完整的动物，也可以是在特殊容器中分离生长的细胞（培养细胞）。为了尽可能有效地工作，测试过程必须使用一种既敏感又与最终使用化学物质的细胞或生物体相关的生物系统。考虑到这些因素，人类胚胎干细胞可能特别适合于寻找影响人类细胞行为的化学物质。胚胎干细胞是从胚胎中提取的培养细胞，为发育过程提供了模型。像胚胎一样，它们对影响自我更新、分化和凋亡的分子高度敏感。计划中的项目将调查人类胚胎干细胞在使用大量不同的化学物质处理后的行为，这些化学物质可能会干扰关键的生物过程。基于这项工作的结果，可以开发研究和控制这些以及其他人类细胞类型的新方法，从而使科学和医学都受益。

Cells use complicated biochemical mechanisms to control their behaviour and tools that interfere with these processes allow scientists to examine how cells work. This leads to a better understanding of biology and in some cases, can provide new diagnostic and treatment methods for disease. Stem cells, and in particular, embryonic stem cells have been the focus of intense scientific research over recent years. Stem cells are defined by an ability to self renew- a process of division that produces two new cells that are identical to the original. This is important in generating an appropriate number of cells during embryonic development and in adult systems where cells are regularly lost. Stem cells can also differentiate- a process of change that leads to the formation of a cell type whose characteristics are different to the original. This generates the diversity of cells (e.g. muscle, nerve, liver) required to form and maintain the organs and tissues of the body. Another possibility is for stem cells or their derivatives to undergo programmed cell death- a process called apoptosis- which prevents over-production of cells and can eliminate those that have suffered severe damage. Maintaining the correct balance between self renewal, differentiation and apoptosis is an essential feature of multicellular organisms. At the most basic level, this balance is controlled by gene expression. Selective use of some but not all parts of the cells' DNA causes changes in the relative amounts of particular proteins that are produced. This, in turn, affects biochemical reactions within cells and alters their behaviour. A number of methods have been developed that can artificially control gene expression, allowing the function of individual genes to be examined. However, the techniques are time consuming and in some cases, unreliable or their effects short lived. Methods that avoid these problems would help scientists carry out their research more effectively. One possibility is found in the form of chemical agents. Because of their enormous diversity of shape, size and composition, chemical agents are not limited to affecting genes and gene expression. With appropriate molecular structures, any cellular component can theoretically be targeted and its function modified. Also, chemicals can simply be added to a biological system without any requirement for complicated preparation, and the scale of the effect can be controlled by varying the dose. Finding chemicals that are capable of producing effects on specific biological targets is difficult. Methods to design chemicals from scratch that alter the function of particular components of a cell are not reliable. Instead, the most successful approaches involve testing a large number of different, ready-made chemicals to identify those that cause a change in behaviour within a biological system; this may be a whole animal or alternatively, cells grown in isolation in a special container (cultured cells). In order to work as effectively as possible, the testing process must use a biological system that is both sensitive and also relevant to the cells or organism in which the chemicals will eventually be used. With these considerations in mind, human embryonic stem cells are likely to be particularly suitable for finding chemicals that affect the behaviour of human cells. Embryonic stem cells are cultured cells derived from embryos that provide a model of the development process. Like embryos, they are highly sensitive to molecules that affect self renewal, differentiation and apoptosis. The planned project will investigate the behaviour of human embryonic stem cells following treatment with a large number of different chemicals that are likely to interfere with key biological processes. Based upon the results of this work, new ways of both investigating and controlling these and also other human cell types can be developed, benefiting both science and medicine.