Kinetics of cell division in normal and malignant epidermis

所有的生物组织，如皮肤，都是由细胞构成的。在各种不同的细胞类型中，干细胞扮演着一种非常特殊的角色，它在分裂时保留了产生相同副本的能力，并转变为功能特定的细胞，这一过程被称为分化。因此，干细胞对发育至关重要，并有望在组织维护和修复中发挥关键作用。通常，每个组织都由许多不同类型的细胞组成，每种细胞都有特定的功能。生物科学的主要挑战之一是了解干细胞及其后代如何维持组织的功能。然而，对组织的细胞组织的研究并没有揭示细胞的谱系，也就是说，通常很难将干细胞与其他类型的细胞区分开来，也不可能追踪给定细胞的祖先。这一建议旨在利用现代基因标记技术来研究表皮（皮肤最外层）和其他组织类型中的细胞命运。通过对DNA进行基因改造，可以培育出一种小鼠品系，其中一小部分皮肤细胞可以被诱导表达黄色荧光蛋白，从而使它们及其后代在显微镜下可以被检测到为黄色染色的细胞斑块。通过计算这些被称为克隆的标记细胞簇中的细胞数量，统计分析方法（在物理和数学科学领域更为熟悉）可以用来揭示不同的细胞类型、细胞分裂率和途径，并最终解决表皮维持的机制。有趣的是，最近使用这些技术的研究表明，表皮符合一个非常简单的随机过程，只涉及一种类型的分裂细胞群，推翻了科学文献中长期持有的教条。这些初步研究为研究其他系统（如人类和青蛙）中的组织维持提供了一个平台，并详细探讨了早期肿瘤生长的机制和药物递送的影响。

All biological tissues, such as skin, are made from cells. Amongst the variety of different cell types, stem cells assume a very special role retaining the ability to produce identical copies of themselves when they divide, and to turn into function-specific cells, a process known as differentiation. As such, stem cells are crucial for development and are expected to play a key role in tissue maintenance and repair. Typically, each tissue is comprised of many different cell types, each having a specific function. One of the main challenges in biological sciences is to understand how stem cells and their progeny function to maintain tissue. However, studies of cellular organisation of tissue do not reveal the lineage of cells, i.e. it is often difficult to distinguish stem cells from other cell types and impossible to trace the ancestry of a given cell.This proposal is designed to take advantage of modern genetic labelling techniques to study cell fate in the epidermis, the outer most layers of skin, and in other tissue types. By genetic modification of the DNA, a strain of mice can be developed where a fraction of skin cells can be induced to express a yellow fluorescent protein, allowing they and their progeny to be detected under the microscope as patches of yellow-stained cells. By counting the number of cells in these labelled cell clusters, known as clones, methods of statistical analysis, more familiar in the realm of physical and mathematical sciences, can be applied to reveal different cell types, cell division rates and pathways and, ultimately, to resolve the mechanism of epidermal maintenance. Intriguingly, recent studies using these techniques have revealed that the epidermis conforms to a remarkably simple random process involving only one type of dividing cell population, overturning a long-held dogma in the scientific literature. These preliminary studies provide a platform to investigate tissue maintenance in other systems, such as humans and frogs, and to explore in detail the mechanism of early tumour growth and the effects of drug delivery.