The regenerative response to tissue necrosis

对组织坏死的再生反应

基本信息

批准号：
10215586
负责人：
Robin Harris
金额：
$ 18.48万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-13 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10215586
关键词：
Ablation Adult Apoptosis Apoptotic Behavior Biological Assay Bone Tissue Cell Death Cell Death Process Cell Death Signaling Process Cells Cessation of life Congenital Abnormality Dinoprostone Disease Drosophila genus Embryonic Development Epigenetic Process Erinaceidae Event Gene Expression Genes Genetic Genetic Transcription Growth and Development function Hepatocyte Homeostasis Human Development Immunofluorescence Immunologic Impairment In Situ Hybridization Infection Inflammation Inherited Injury Investigation Label Lead Libraries Liver Liver Regeneration Malignant Neoplasms Membrane Methods Modeling Morbidity - disease rate Morphology Mus Muscle Myocardial Infarction Natural regeneration Necrosis Organ Play RNA RNA Interference RNA interference screen Recovery Regenerative capacity Regenerative research Regenerative response Reporter Genes Role Signal Transduction Signaling Molecule Site Stroke System Testing Tissues Transgenic Organisms Vertebrates Wing Work base blastema cell behavior cell injury experimental study genetic approach genetic manipulation genome sequencing genome-wide healing human disease improved in vivo regeneration insight ischemic injury liver injury necrotic tissue novel novel therapeutic intervention regeneration following injury regenerative response screening tissue regeneration tool virtual whole genome wound wound healing

项目摘要

PROJECT SUMMARY Cell death has a critical role in wound healing and regeneration following injury, disease or infection. Apoptosis at a site of injury can significantly impact the behavior of surrounding cells, as signals produced by dying cells can induce inflammation, proliferation and dictate the survival of their neighbors. These activities can therefore directly regulate a tissue’s ability to recover from damage. For example, following liver injury in mice, signaling molecules produced by dying hepatocytes drive regenerative proliferation. Thus, a better understanding of how a tissue responds to damage-signals could uncover novel therapeutic interventions to improve wound healing and regeneration. Although advances have been made in understanding how apoptosis contributes to regeneration, little is known about whether non-apoptotic forms of cell death, such as necrosis, might have a similar role. Necrosis occurs in numerous human diseases, particularly following ischemic injury (stroke and heart attack), infections and cancer. Regeneration following necrotic cell death is significantly more variable than that induced by apoptosis, but has been documented in various tissues, suggesting that as yet unidentified and distinct mechanisms might exist in each context. Thus, the aim of this work is to characterize the fundamental genetic mechanisms that lead to regeneration following necrosis versus apoptosis. Evidence that signals from apoptotic cells impact surrounding tissues first originated from studies of the larval wing primordia in Drosophila, an attractive and powerful model to study regeneration. The genetic tools available in Drosophila have led to important insights into the genetic events necessary for regeneration. Studies of regeneration in the larval wing commonly rely on genetic ablation, an efficient and robust approach that permits spatially and temporally controlled cell death to be induced in tissues. However, despite its advantages, this method is also limited in the genetic manipulations that can be achieved, and is lacking the ability to study non- apoptotic forms of tissue loss, such as necrosis. To overcome these problems we have established a new method, DUAL Control, that allows us to induce necrosis or apoptosis in the developing wing primordia, stimulating a regenerative response to either type of damage. Our initial investigations suggest that necrosis and apoptosis lead to dramatically different gene expression changes and morphologies in the surrounding tissue. Importantly, however, regeneration occurs in both situations. As an advance on previous approaches, this novel system also allows us to target genetic manipulations specifically to the surrounding regenerating tissue, independent of ablation. These experiments can therefore take advantage of the large purpose-built RNAi screening libraries available in Drosophila to interrogate regenerating cells directly. We propose to use this new method to characterize the genetic response to damage that leads to successful regeneration following necrosis compared to apoptosis, with a view to identifying novel regulators of regenerative capacity in each context.

项目摘要细胞死亡在受伤，疾病或感染后的伤口愈合和再生中具有关键作用。凋亡在损伤部位，由于垂死细胞产生的信号会显着影响周围细胞的行为可以诱发炎症，扩散并决定其邻居的生存。因此，这些活动可以直接调节组织从损害中恢复的能力。例如，在小鼠肝损伤后，信号传导通过死亡的肝细胞产生的分子驱动再生增殖。那是更好地理解如何组织对损伤信号的反应可能会发现新的治疗干预措施以改善伤口愈合和再生。尽管在了解凋亡如何有助于再生，对细胞死亡的非凋亡形式（例如坏死）知之甚少相似的角色。坏死发生在许多人类疾病中，特别是在缺血性损伤后（中风和心脏病发作），感染和癌症。坏死细胞死亡后的再生比凋亡引起的诱导，但已在各种组织中进行了记录，这表明尚未确定和在每种情况下可能存在不同的机制。这项工作的目的是表征基本在坏死与凋亡后导致再生的遗传机制。凋亡细胞的信号影响周围组织的证据首先源自幼虫的研究果蝇中的翼产物，这是一种研究再生的有吸引力而有力的模型。可用的遗传工具在果蝇中，引发了对再生所需的遗传事件的重要见解。研究幼虫翼的再生通常依赖于遗传消融，这是一种有效而健壮的方法在空间和暂时控制的细胞死亡中，可在组织中诱导。但是，目的地的优势，这个方法在可以实现的遗传操作中也受到限制，并且缺乏研究非研究的能力组织损失的凋亡形式，例如坏死。为了克服这些问题，我们已经建立了一个新的方法，双重控制，使我们能够在发育中的机翼原基中诱导坏死或凋亡，刺激对任何一种损伤的再生反应。我们的初步调查表明坏死和凋亡导致周围组织中的基因表达变化和形态发生了巨大不同。但是，重要的是，在两种情况下都会发生再生。作为先前方法的进步，这本小说系统还允许我们针对周围的再生组织的遗传操作，独立于消融。因此，这些实验可以利用大型专用RNAi 筛选果蝇可用的文库直接询问再生细胞。我们建议使用这个新的表征对损伤的遗传反应的方法，导致坏死后成功再生与凋亡相比，以确定每种情况下再生能力的新调节剂。