Understanding Necrosis-Induced Tissue Regeneration

了解坏死诱导的组织再生

• 批准号: 10504552
• 负责人: Robin Harris
• 金额: $ 31.51万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10504552
• 关键词: Ablation; Address; Adult; Apoptosis; Apoptotic; Behavior; Burn injury; Cell Death; Cells; Dinoprostone; Disease; Drosophila genus; Embryonic Development; Epigenetic Process; Erinaceidae; Event; Frostbite; Generations; Genes; Genetic; Growth and Development function; Health; Hepatocyte; Homeostasis; Human; Human Development; Impairment; Infection; Injury; Lead; Liver; Liver Regeneration; Lytic; MAPK8 gene; Membrane; Modeling; Molecular; Mus; Myocardial Infarction; Natural regeneration; Necrosis; Organ; Outcome; Pathway interactions; Pattern; Play; Process; Recovery; Regenerative capacity; Role; Signal Transduction; Signaling Molecule; System; Tissues; Traumatic injury; Wing; Work; apoptosis inducing factor; base; cell type; disc regeneration; experimental study; genetic approach; genetic manipulation; genome sequencing; healing; imaginal disc; improved; in vivo; injury recovery; insight; ischemic injury; next generation sequencing; novel; novel therapeutic intervention; programs; regeneration following injury; regenerative; release factor; repaired; response; stroke-like episode; tissue regeneration; tissue repair; tool; transcriptomics; virtual; whole genome; wound

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.

项目摘要 细胞死亡在受伤或疾病后的人类发展和恢复中具有关键作用。这是 因为垂死的细胞产生的信号可以显着影响周围细胞的行为。这 这些信号的身份和后果是多种多样的和背景的，但许多人已知 调节受伤后相邻细胞的存活，活性和增殖。因此，更好的理解 关于垂死细胞如何影响存活组织的如何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。 虽然这种信号传导现象在凋亡细胞死亡中已经表征了，但尚不清楚是否清楚 不受管制的细胞死亡形式（例如坏死）对组织行为和修复具有相似的影响。 坏死是细胞的快速，无序的死亡，可以在任何组织中发生，并且对许多人来说都是核心 疾病，包括创伤性伤害（烧伤，冻伤），感染和缺血性损伤，例如中风和心脏 攻击。但是，已经确定了从坏死细胞释放的几个因素，但是，其他信号的身份 以及它们是否影响恢复尚待检查。该提议的目的是调查如何 坏死性伤口会影响周围组织的恢复和再生。 垂死细胞的信号影响附近组织的证据首先源自幼虫的研究 果蝇中的翼产物，称为想象盘。这些组织具有明显的再生能力 研究导致对损伤诱导组织所需的遗传事件的重要见解 恢复。但是，这些研究中的大多数研究了凋亡引起的再生，从而限制了我们的理解 细胞死亡如何影响存活的组织对这种类型的伤害。为了克服这一限制，我们有 建立了一种遗传工具，使我们能够在发育中的机翼盘中触发坏死或凋亡，以及 从遗传上操纵周围的细胞，以响应每种损伤。 使用此工具，我们发现碟片在每种情况下都成功再生，但通过不同的机制。 值得注意的是，坏死会导致距伤口距离的广泛凋亡细胞死亡。这种坏死 - 诱导的凋亡或NIA是驱动再生增殖所必需的，因此对于适当而言至关重要 恢复。 NIA的原因及其如何促进再生是未知的。在这里，我们建议 表征导致坏死后成功再生的遗传反应。 尼亚。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， 并全面地表征坏死诱导的再生计划，该计划使用整体导致NIA 基因组测序方法。这些实验的结果一起将有助于我们的基本 了解组织修复对坏死的理解，最终对于发展新型是必不可少的 治疗坏死伤并促进人类再生的治疗方法。