Genetic Analysis of Dedifferentiation

描述（由申请人提供）：去分化被定义为细胞从高度分化到低分化状态的进展。在器官再生、癌症、哮喘和心脏病中都观察到它，并且与干细胞相关的过程也有联系。由于缺乏遗传上可处理的系统，因此很难在动物中研究去分化。直到最近，人们甚至还不清楚去分化是由专门的有序机制调控的，还是仅仅是发育特性的随机、大规模丧失。这个问题很关键，因为规范过程比随机过程更容易进行调查。最近对盘基骨菌、果蝇和大鼠的研究表明，去分化是一个受调控的过程，为系统的遗传研究开辟了领域。研究盘基骨柱脱分化的基础可能会涉及其他真核生物的同源机制。本项目拟通过遗传筛选研究盘基骨鞘去分化的遗传基础。这是一个高风险/高收益的提议，但风险是概念性的，而不是技术性的。研究人员已经进行了初步的基因筛选，产生了有趣的突变体，因此这项技术运行良好。被发现的基因和机制的性质和普遍性仍有待确定，但收获可能是巨大的。通过为去分化相关疾病的研究和治疗提供分子靶点，确定相关机制将彻底改变这一领域。去分化与癌症、哮喘和心脏病等人类疾病有关。它也与成体干细胞更新过程有关。研究盘基骨鞘去分化的基础有望在人类中找到类似的机制。通过为去分化相关疾病的研究和治疗提供分子靶点，确定相关机制将彻底改变这一领域。

DESCRIPTION (provided by applicant): Dedifferentiation is defined as the progression of cells from a more differentiated to a less differentiated state. It is observed in organ regeneration, cancer, asthma, and heart disease and has been linked to stem cell-related processes as well. Dedifferentiation is difficult to study in animals because of paucity in genetically tractable systems. Until recently it was not even clear whether dedifferentiation was regulated by dedicated orderly mechanisms or merely a stochastic, wholesale loss of developmental properties. This question is critical because regulated processes are more accessible to investigation than stochastic ones. Recent work in Dictyostelium, Drosophila and rats showed that dedifferentiation is a regulated process, opening the field to methodical genetic investigation. Studying the basics of Dictyostelium dedifferentiation might implicate homologous mechanisms in other eukaryotes. The proposed project will investigate the genetic basis of Dictyostelium dedifferentiation through genetic screens. This is a high-risk/high-gain proposal, but the risk is conceptual rather than technical. The investigators have already performed pilot genetic screens that yielded interesting mutants, so the technology works well. The nature and generality of the genes and mechanisms that would be found remains to be determined, but the gain might be enormous. Identification of relevant mechanisms would revolutionize the field by providing molecular targets for research and therapy of dedifferentiation-related disorders. Dedifferentiation is involved in human diseases such as cancer, asthma, and heart disease. It is also related to processes involved in adult stem cell renewal. Studying the basics of Dictyostelium dedifferentiation is expected to implicate homologous mechanisms in humans. Identification of relevant mechanisms would revolutionize the field by providing molecular targets for research and therapy of dedifferentiation-related disorders.