Understanding Necrosis-Induced Tissue Regeneration

项目摘要 细胞死亡在损伤或疾病后的人类发育和恢复中具有关键作用。这是 因为垂死的细胞会产生信号，这些信号会显著影响周围细胞的行为。的 这些信号的身份和后果是多种多样的，并取决于上下文，但已知许多信号 调节损伤后邻近细胞的存活、活性和增殖。更好地理解 死亡细胞如何影响存活组织的研究可能会发现新的治疗干预措施，以改善愈合， 损伤或疾病后的再生。 虽然这种信号传导现象的特征在于凋亡性细胞死亡，但尚不清楚 不受控制的细胞死亡形式如坏死对组织行为和修复具有类似的影响。 坏死是细胞的快速、无序死亡，其可发生于任何组织中，并且是许多人类疾病的核心。 条件，包括创伤性损伤（烧伤，冻伤），感染和缺血性损伤，如中风和心脏 攻击已经确定了坏死细胞释放的几种因子，然而， 是否影响经济复苏还有待检验。本提案的目的是研究如何 坏死伤口影响周围组织以影响恢复和再生。 死亡细胞的信号影响附近组织的证据首先来自对幼虫的研究， 果蝇的翅原基，叫做成虫盘。这些组织具有显著的再生能力， 对这一点的研究使人们对损伤诱导组织所必需的遗传事件有了重要的了解， 复苏然而，大多数这些研究检查骨化诱导的再生，限制了我们的理解 细胞死亡如何影响这种损伤的幸存组织。为了克服这一局限性，我们 建立了一种遗传工具，使我们能够在发育中的翼盘中触发坏死或凋亡， 以遗传方式操纵周围细胞对每种损伤的反应。 有了这个工具，我们发现椎间盘在每种情况下都能成功再生，但机制不同。 值得注意的是，坏死导致离伤口一定距离处的广泛的凋亡性细胞死亡。坏死- 诱导的细胞凋亡或NiA是驱动再生增殖所必需的，因此对于适当的细胞增殖至关重要。 复苏NiA的原因以及它如何促进再生目前尚不清楚。在此，我们建议 描述导致坏死后成功再生的遗传反应，重点关注 的NiA。我们的工作旨在确定坏死如何导致NiA，了解NiA如何促进再生， 并全面表征坏死诱导的再生程序，导致NiA使用整个 基因组测序方法。总之，这些实验的结果将有助于我们的基本 理解组织修复对坏死的反应，这对于开发新的 用于治疗人类坏死伤口和促进再生的治疗方法。

Project Summary Cell death has a critical role in human development and recovery following injury or disease. This is because dying cells produce signals that can significantly impact the behavior of the surrounding cells. The identity and consequences of these signals are diverse and context dependent, but many are known to regulate the survival, activity and proliferation of neighboring cells following injury. Thus, a better understanding of how dying cells impact surviving tissue could uncover novel therapeutic interventions to improve healing and regeneration following injury or disease. While this signaling phenomenon has been characterized in apoptotic cell death, it is unclear whether unregulated forms of cell death, such as necrosis, have a similar impact on tissue behavior and repair. Necrosis is the rapid, disordered death of cells, which can occur in any tissue and is central to many human conditions, including traumatic injuries (burns, frostbite), infections, and ischemic injuries like strokes and heart attacks. Several factors released from necrotic cells have been identified, however, the identity of other signals and whether they influence recovery has yet to be examined. The aim of this proposal is to investigate how necrotic wounds impact surrounding tissues to influence recovery and regeneration. Evidence that signals from dying cells impact nearby tissues first originated from studies of the larval wing primordia in Drosophila, called imaginal discs. These tissues have significant regenerative capacity, the study of which has led to important insights into the genetic events necessary for damage-induced tissue recovery. However, most of these studies examine apoptosis-induced regeneration, limiting our understanding of how cell death impacts surviving tissue to this type of injuries. To overcome this limitation, we have established a genetic tool that allows us to trigger either necrosis or apoptosis in the developing wing disc, and to genetically manipulate the surrounding cells that respond to each type of damage. With this tool we found that discs successfully regenerate in each case, but via different mechanisms. Notably, necrosis leads to widespread apoptotic cell death at a distance from the wound. This necrosis- induced apoptosis, or NiA, is necessary to drive regenerative proliferation and is therefore critical for proper recovery. The cause of NiA and how it promotes regeneration are currently unknown. Here, we propose to characterize the genetic response that leads to successful regeneration following necrosis focusing on the role of NiA. Our work aims to identifying how necrosis leads to NiA, understand how NiA promotes regeneration, and comprehensively characterize the necrosis-induced regeneration program that results in NiA using whole genome sequencing approaches. Together, the results of these experiments will contribute to our fundamental understanding of tissue repair in response to necrosis, which is ultimately essential for developing novel therapeutic approaches to treat necrotic wounds and promote regeneration in humans.