Understanding Necrosis-Induced Tissue Regeneration

项目摘要 细胞死亡在人类受伤或疾病后的发育和恢复中起着至关重要的作用。这是 因为濒临死亡的细胞产生的信号会显著影响周围细胞的行为。这个 这些信号的身份和结果是不同的，并取决于背景，但已知的许多信号 调节损伤后邻近细胞的存活、活性和增殖。因此，更好地理解 死亡细胞如何影响存活组织的研究可以发现新的治疗干预措施，以改善愈合和 受伤或疾病后的再生。 虽然这种信号现象的特征是细胞凋亡，但目前还不清楚 不受控制的细胞死亡形式，如坏死，对组织行为和修复也有类似的影响。 坏死是细胞的快速、无序死亡，它可以发生在任何组织中，是许多人类的中心。 情况，包括创伤性损伤(烧伤、冻伤)、感染以及中风和心脏等缺血性损伤 袭击。已经确定了几个从坏死细胞释放的因子，然而，其他信号的同一性 它们是否会影响经济复苏还有待检验。这项提案的目的是调查如何 坏死性伤口影响周围组织，影响恢复和再生。 来自死亡细胞的信号影响附近组织的证据最初来自对幼虫的研究 果蝇的翅膀原基，称为想象盘。这些组织具有显著的再生能力， 对它的研究已经导致了对损伤诱导组织所必需的遗传事件的重要洞察 恢复。然而，这些研究大多研究了细胞凋亡诱导的再生，限制了我们的理解 细胞死亡如何影响存活的组织到这种类型的损伤。为了克服这一限制，我们有 建立了一种基因工具，允许我们触发发育中的翼盘的坏死或凋亡，以及 从基因上操控周围对每种损伤做出反应的细胞。 有了这个工具，我们发现在每种情况下，光盘都能成功再生，但机制不同。 值得注意的是，在远离伤口的地方，坏死会导致广泛的细胞凋亡性死亡。这种坏死- 诱导细胞凋亡，或称NIA，是驱动再生增殖所必需的，因此对正常的 恢复。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，重点关注其作用 妮娅的名字。我们的工作旨在确定坏死是如何导致NIA的，了解NIA如何促进再生， 并全面描述了导致NIA的坏死诱导再生计划 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 了解组织修复对坏死的反应，这是开发新技术的最终关键 治疗人类坏死性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.