Identifying novel strategies to promote tissue regeneration

描述(申请人提供)：许多成人人体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取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纽特等动物身上再生。由于同一类型的组织可以在一种动物身上再生，但不能在另一种动物身上再生，所以不同物种的相似组织之间一定存在重要的差异，在一种情况下允许再生，而在另一种情况下不允许再生。挑战是找到方法来操纵缺乏或已经失去再生能力的组织，使其能够再次再生生长。通过对果蝇、酵母和线虫的遗传学研究，阐明了调控胚胎发育、细胞周期调节和细胞凋亡的基本机制。然而，到目前为止，利用这些模式生物来研究组织再生的调节机制一直是困难的。我们最近开发了一种系统，允许使用果蝇遗传学工具来识别调节再生生长能力的基因。通过表达一种可以以空间和时间受限的方式杀死细胞的基因，我们可以有效地消融部分果蝇想象盘，并允许它们在不需要复杂的手术操作的情况下原位再生。再生在幼虫发育的特定阶段有效发生，但不能超过第三龄幼虫的临界点。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的表达变化。我们将进行大规模的基因突变筛查，寻找特定基因的突变，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以用来增强组织再生生长能力的策略。对于公共卫生，这个项目的目的是找到方法，使受损组织被正常和功能组织(再生)取代。这在治疗心脏病发作、中风或退行性疾病的患者中将是重要的。

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. to Public Health This project is aimed at finding ways to get damaged tissue to be replaced by normal and functional tissue (regeneration). This would be important in the treatment of patients who have had heart attacks, strokes or degenerative diseases.