Complexity and the Wound Healing Response

项目摘要 治愈的能力对人类健康至关重要。人类显著的伤口愈合能力（以及 事实上所有动物）是一个复杂的过程。基因组研究表明，超过5000个mRNA 转录物在伤口愈合过程中改变表达模式，并且有十几种细胞类型参与其中。 尽管涉及大量的细胞和分子，但伤口的复杂性的许多方面都是复杂的。 治愈并没有得到很好的理解。系统方法已经建立了参与基因的广度， 愈合，并比较了不同类型伤口的基因谱。然而，许多关于 伤口内部的网络和相互作用仍然没有答案。这里提出的研究夫妇小说 定量方法与基础生物学研究，以检查与复杂性有关的几个问题， 以及组织修复过程的多样性。该研究计划涉及三个独立的，但 补充问题。问题1问：差异的基础是什么样的调节途径， 在皮肤和口腔粘膜中观察到的部位特异性愈合？我们和其他人的研究表明， 口腔粘膜中的伤口表现出更快的上皮再形成、减少的炎症、更好的发育 血管生成反应，并且与皮肤相比疤痕形成较少。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 导致这两种组织的不同愈合。研究方法采用最先进的 算法和体内实验，以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：治疗中的冗余级别是多少 伤口？这个问题通过评估分子冗余来探索愈合的稳健性。冗余 已经被假定为存在于伤口中作为“故障安全”机制，确保伤口愈合进行，即使 一些关键元件在功能上失活。问题2的基本概念是， 当特定基因被删除时，伤口会发生补偿。该方法使用基因缺陷 （“敲除”）小鼠以检查愈合伤口中冗余的程度。问题3：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的计算 建模框架称为动态细胞有限元模型（DyCelFEM），以开发一个模型， 预测愈合反应的上皮修复。该研究计划将该模型扩展到包括 伤口愈合的其他特征，如血管生成。完成后，该模型可用于测试 单个或多个因素的扰动对愈合结果的影响。这种先进的模式将是一个 这是一个强大的工具，可以帮助我们了解慢性伤口的病理生理学， 治疗学的发展。总的来说，研究计划的三个要素解决了伤口如何愈合， 治疗是在网络层面上进行管理的，并将揭示调节治疗能力的关键特征。

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.