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.

项目概要 细胞死亡在人类发育和受伤或疾病后的恢复中起着至关重要的作用。这是 因为垂死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并且依赖于上下文，但许多信号已知 调节损伤后邻近细胞的存活、活性和增殖。从而更好地理解 研究垂死的细胞如何影响幸存的组织可能会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已在细胞凋亡中得到表征，但尚不清楚是否 不受控制的细胞死亡形式，例如坏死，对组织行为和修复也有类似的影响。 坏死是细胞快速、无序的死亡，它可以发生在任何组织中，并且是许多人类的核心。 疾病，包括外伤（烧伤、冻伤）、感染以及中风和心脏等缺血性损伤 攻击。已鉴定出坏死细胞释放的几种因子，但是其他信号的身份 它们是否影响恢复还有待检验。该提案的目的是研究如何 坏死伤口影响周围组织，影响恢复和再生。 垂死细胞的信号影响附近组织的证据首先源自对幼虫的研究 果蝇的翅原基，称为成虫盘。这些组织具有显着的再生能力 其研究使人们对损伤引起的组织所必需的遗传事件有了重要的了解 恢复。然而，这些研究大多数都检查细胞凋亡诱导的再生，限制了我们的理解 研究细胞死亡如何影响存活组织以应对此类损伤。为了克服这个限制，我们有 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，并且 基因操纵周围细胞对每种类型的损伤做出反应。 通过这个工具，我们发现光盘在每种情况下都可以成功再生，但通过不同的机制。 值得注意的是，坏死导致距伤口一定距离处广泛的细胞凋亡。这种坏死—— 诱导细胞凋亡（NiA）是驱动再生增殖所必需的，因此对于适当的细胞凋亡至关重要 恢复。 NiA 的病因及其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 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，该程序导致 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础研究 了解坏死后的组织修复，这对于开发新的新方法至关重要 治疗坏死伤口并促进人类再生的治疗方法。