Complexity and the Wound Healing Response

复杂性和伤口愈合反应

• 批准号: 10322976
• 负责人: LUISA A DIPIETRO
• 金额: $ 39.43万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10322976
• 关键词: Address; Algorithms; Animals; Cells; Cicatrix; Collaborations; Complex; Computer Models; Couples; Disease; Elements; Epithelial; Event; Exhibits; Financial compensation; Functional disorder; Genes; Genomics; Health; Human; Inflammation; Knockout Mice; Messenger RNA; Modeling; Molecular; Oral mucous membrane structure; Outcome; Pattern; Process; Regulatory Pathway; Research; Site; Skin; System; Testing; Tissues; Transcript; angiogenesis; biological research; cell type; chronic wound; epithelial repair; experimental study; healing; in vivo; novel; response; skin regeneration; skin wound; therapeutic development; tissue repair; tool; transcription factor; transcriptome; wound; wound healing

Project Summary The ability to heal is essential for human health. The remarkable wound healing capacity of humans (and indeed of all animals) is a complicated process. Genomic studies suggest that more than 5000 mRNA transcripts change expression patterns during wound healing, and more than a dozen cell types participate. Despite the large number of cells and molecules that are involved, many aspects of the complexity of wound healing are not well understood. Systems approaches have established the breadth of genes involved in healing, and have compared gene profiles in different types of wounds. Yet many questions about the networks and interactions within wounds are still unanswered. The research proposed here couples novel quantitative approaches with basic biologic research to examine several questions related to the complexity and diversity of the events that compose tissue repair. The research plan addresses three separate but complementary questions. Question 1 asks - What are the regulatory pathways that underlie the differential, site specific healing that is seen in skin versus oral mucosa? Studies by us and others have shown that wounds in the oral mucosa exhibit faster re-epithelialization, reduced inflammation, a better-developed angiogenic response, and less scar formation as compared to skin. Oral mucosal and skin wounds also have distinctive transcriptomes. The central concept underlying Question 1 is that key transcription factors are responsible for the differential healing seen in these two tissues. The research approach uses state-of-the-art algorithms and in vivo experiments to discover and validate the transcription factors (and their networks) that distinguish oral mucosal and skin healing. Question 2 asks - What is the level of redundancy in healing wounds? This question explores the robustness of healing by assessing molecular redundancy. Redundancy has been posited to exist in wounds as a “fail-safe” mechanism, insuring that wound healing proceeds even if some key elements are functionally inactivated. The underlying concept for Question 2 is that significant gene compensation occurs in wounds when specific genes are deleted. The approach uses genetically deficient (“knockout”) mice to examine the extent of redundancy in healing wounds. Question 3 asks- Can quantitative models be used to predict wound healing outcomes? Our ongoing collaboration utilizes a novel computational modeling framework called the dynamic cellular finite-element model (DyCelFEM) to develop a model of epithelial repair that is predictive of healing responses. The research plan extends the model to include additional features of wound healing, such as angiogenesis. When completed, the model can be used to test the effect of perturbations of single or multiple factors on healing outcomes. This advanced model will be a powerful tool that can contribute to our understanding of both the pathophysiology of chronic wounds and the development of therapeutics. Taken together, the three elements of the research plan address how wound healing is governed at a network level, and will uncover critical features that regulate the ability to heal.

项目概要 治愈能力对于人类健康至关重要。人类卓越的伤口愈合能力（以及 实际上对于所有动物来说）是一个复杂的过程。基因组研究表明超过 5000 个 mRNA 转录本在伤口愈合过程中改变表达模式，十多种细胞类型参与其中。 尽管涉及大量细胞和分子，但伤口的许多方面都很复杂 治疗还没有被很好地理解。系统方法已经确定了参与的基因的广度 愈合，并比较了不同类型伤口的基因谱。但仍有很多疑问 伤口内的网络和相互作用仍然没有答案。这里提出的研究结合了小说 结合基础生物学研究的定量方法来研究与复杂性相关的几个问题 以及构成组织修复的事件的多样性。该研究计划涉及三个独立但 补充问题。问题 1 提出——造成差异的监管途径是什么？ 皮肤与口腔粘膜中所见的部位特异性愈合？我们和其他人的研究表明 口腔粘膜的伤口表现出更快的上皮化速度、减少的炎症、更好的发育 与皮肤相比，血管生成反应更少，疤痕形成更少。口腔粘膜和皮肤伤口也有 独特的转录组。问题 1 的核心概念是关键转录因子是 造成这两种组织中愈合差异的原因。研究方法采用最先进的 算法和体内实验来发现和验证转录因子（及其网络） 区分口腔粘膜和皮肤愈合。问题 2 提出——治疗中的冗余程度是多少 伤口？该问题通过评估分子冗余来探讨愈合的稳健性。冗余 已被认为作为一种“自动防故障”机制存在于伤口中，即使在 一些关键元件在功能上失活。问题 2 的基本概念是重要基因 当特定基因被删除时，伤口中就会发​​生补偿。该方法利用基因缺陷 （“敲除”）小鼠来检查伤口愈合过程中的冗余程度。问题3问——能否定量 模型可用于预测伤口愈合结果？我们正在进行的合作利用了一种新颖的计算方法 称为动态细胞有限元模型 (DyCelFEM) 的建模框架，用于开发模型 上皮修复可预测愈合反应。该研究计划将模型扩展至包括 伤口愈合的其他特征，例如血管生成。完成后，模型可用于测试 单个或多个因素的扰动对治疗结果的影响。这种先进的模型将是 强大的工具，可以有助于我们了解慢性伤口的病理生理学和 治疗学的发展。总的来说，研究计划的三个要素解决了如何创伤 治愈是在网络层面进行管理的，并将揭示调节治愈能力的关键特征。