Genetic Analysis of Dedifferentiation

描述(由申请人提供)：去分化定义为细胞从较高分化状态向较低分化状态的进展。它在器官再生、癌症、哮喘和心脏病中被观察到，也与干细胞相关的过程有关。去分化是很难在动物身上研究的，因为在遗传上容易处理的系统中很少。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，还是仅仅是随机的、大规模的发育特性丧失。这个问题至关重要，因为与随机过程相比，受监管的过程更容易被调查。最近在网柄网柄菌、果蝇和大鼠身上的研究表明，去分化是一个受调控的过程，为有条不紊的遗传学研究打开了大门。研究网柄网柄菌去分化的基础可能会在其他真核生物中涉及到类似的机制。这项拟议的项目将通过遗传筛选来研究网柄网柄菌去分化的遗传基础。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试点基因筛查，产生了有趣的突变，因此这项技术运作良好。将发现的基因和机制的性质和一般性仍有待确定，但收益可能是巨大的。相关机制的确定将为去分化相关疾病的研究和治疗提供分子靶点，从而使该领域发生革命性变化。去分化与癌症、哮喘和心脏病等人类疾病有关。它也与成人干细胞更新的过程有关。研究网柄菌去分化的基础有望揭示人类的同源机制。相关机制的确定将为去分化相关疾病的研究和治疗提供分子靶点，从而使该领域发生革命性变化。

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.