Identifying novel strategies to promote tissue regeneration

描述（由申请人提供）：许多成人器官无法修复因受伤或疾病而受损的组织。在心肌梗死、中风和各种退行性疾病之后，没有有效的方法通过再生生长来替代受损或丢失的组织。因此，提高成人组织的再生能力将极大地影响这些医疗条件的临床管理。值得注意的是，这些相同的组织可以在斑马鱼和蝾螈等动物身上再生。由于同一类型的组织可以在一种动物身上再生，而不能在另一种动物身上再生，所以不同物种的类似组织之间一定存在着重要的差异，这种差异可以在一种动物身上再生，而在另一种动物身上却不能。我们面临的挑战是如何找到方法来操纵缺乏或已经失去再生能力的组织，使其再次具有再生生长的能力。通过对果蝇、酵母和秀丽隐杆线虫的遗传研究，阐明了调控胚胎发育、细胞周期调控和细胞凋亡的基本机制。然而，到目前为止，很难利用这些模式生物来研究调节组织再生的机制。我们最近开发了一个系统，该系统允许果蝇遗传学工具用于识别调节再生生长能力的基因。通过表达一种可以在空间和时间上都受到限制的方式杀死细胞的基因，我们可以有效地切除部分果蝇的想象椎间盘，并使它们在原位再生，而不需要复杂的手术操作。再生在幼虫发育的特定阶段是有效的，但在第三个幼虫期不能超过一个临界点。我们建议寻找与再生生长能力丧失相关的生长和细胞周期进程调节因子表达的变化。我们将对特定基因的突变进行大规模的基因筛选，这些突变可以在发育的后期（通常不会发生的时候）实现再生生长。使用这种方法，我们的目标是找到可用于增强组织再生生长能力的策略。

DESCRIPTION (provided by applicant): Many adult human organs are incapable of repairing tissue that has been damaged as a result of injury or disease. Following myocardial infarctions, strokes and a variety of degenerative diseases, there is no effective way of replacing the damaged or lost tissue by regenerative growth. Hence, improving the regenerative capacity of adult tissues would dramatically impact the clinical management of these medical conditions. Remarkably, these same tissues can regenerate in animals such as the zebrafish and the newt. Since the same type of tissue can regenerate in one animal but not another, important differences must exist between similar tissues in different species that allow regeneration in one case but not the other. The challenge is to be able to find ways to manipulate tissue that lacks or has lost the capacity to regenerate to become capable of regenerative growth once again. The basic mechanisms that regulate embryonic development, cell cycle regulation and apoptosis were elucidated using genetic studies in Drosophila, yeast and C. elegans. However, until now, it has been difficult to use these model organisms to study the mechanisms that regulate tissue regeneration. We have recently developed a system that allows the tools of Drosophila genetics to be used to identify genes that regulate the capacity for regenerative growth. By expressing a gene that can kill cells in a manner that is both spatially and temporally restricted, we can efficiently ablate portions of Drosophila imaginal discs and allow them to regenerate in situ without the need for complex surgical manipulations. Regeneration occurs efficiently at specific stages of larval development but cannot occur beyond a critical point during the third larval instar. We propose to look for changes in the expression of regulators of growth and cell-cycle progression that correlate with the loss of capacity for regenerative growth. We will conduct a large-scale genetic screen for mutations in specific genes that can enable regenerative growth at later stages of development (at a time when it normally does not occur). Using this approach we aim to find strategies that can be used to enhance a tissue's capacity for regenerative growth.