Elucidating the Role of Microbial Community Dynamics in Wound Repair and Regeneration

阐明微生物群落动态在伤口修复和再生中的作用

• 批准号: 10026417
• 负责人: Lindsay Robyn Kalan
• 金额: $ 37.43万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10026417
• 关键词: Bacteria; Cells; Chronic; Clinical; Communities; Complex; Ecosystem; Event; Family suidae; Goals; Growth; Health; Human; Immune response; Impaired healing; Impaired wound healing; Infection; Inflammation; Inflammatory Response; Interruption; Knowledge; Mediating; Microbial Biofilms; Molecular; Monitor; Natural regeneration; Necrosis; Organism; Pathogenicity; Pathway interactions; Phenotype; Process; Publishing; Research; Role; Series; Shapes; Signal Transduction; Skin; Skin repair; Structure; Taxonomy; Work; Wound models; chronic wound; fungus; healing; member; microbial; microbial community; microbiome; microbiome research; microbiota; microorganism; microorganism interaction; non-healing wounds; pathogen; programs; repaired; response; skin microbiota; skin wound; symbiont; tissue regeneration; tissue repair; trait; wound; wound environment; wound healing

Project Summary The goal of my research program is to understand the mechanisms underlying how microbial communities assemble in wound tissue and how these communities influence tissue repair pathways in the skin. During normal wound healing, the process that leads to tissue regeneration results from a series of tightly regulated sequential events. In the case of chronic, non-healing wounds, this process is disrupted, leading to a prolonged inflammatory response and stalled healing. Key recent advances in the understanding of impaired wound healing is the knowledge that complex microbial communities (a microbiome), exist within the wound tissue. Microbiomes in the wound tissue do not always cause clinical infection, but it is thought that they might sustain inflammation, further impairing healing pathways and skin repair. The majority of all published wound microbiome studies profile the taxonomic composition, but it is unclear how these diverse microbial communities actually interact with and influence host repair pathways. Thus, the extent of microbial influences on tissue regeneration remains to be resolved. The skin itself is a diverse ecosystem harboring beneficial microbial symbionts that function to regulate host immune responses and protect against pathogen colonization. We and others have shown that chronic wound microbiomes are comprised largely of skin commensals co-existing with skin pathogens and environmental organisms. This finding suggests that the benefits normally conferred by the skin microbiota may be lost in a wound environment, and it also highlights our incomplete understanding of how microbial interactions shape host health. The proposed research program will define the processes by which structured microbial communities form in wound tissue and will identify the molecular mechanisms governing inter-species interactions within these communities. We will accomplish this using a live ex vivo human skin wound model that we have developed to directly monitor growth dynamics of multi-species consortium and immune responses of resident skin cells. We can then determine how wound healing pathways shift in response to the makeup of the community and phenotypic traits, such as formation of microbial biofilm, in a porcine model of wound healing. We will also build upon our recent discovery that members of the healthy skin microbiota are exceptionally good at inhibiting the growth of diverse fungi. When placed in an ecological context, this finding is not surprising, as the skin has very low fungal diversity. However, we have also shown that fungal colonization and interactions with bacteria are significantly associated with necrosis of wound tissue and delayed healing. We will characterize the metabolites produced by the healthy skin microbiota mediating competitive interactions with fungi and determine their role in modulating microbial community dynamics both on healthy skin and within wound microbiomes containing fungi and bacteria in close interaction. Our studies will advance our understanding of impaired wound healing and will uncover fundamental processes governing dynamics of microbial community assembly.

项目摘要 我的研究项目的目标是了解微生物群落 在伤口组织中组装以及这些社区如何影响皮肤中的组织修复途径。期间 正常的伤口愈合，导致组织再生的过程是由一系列严格调节的 连续事件在慢性不愈合伤口的情况下，这一过程被破坏，导致长时间的伤口愈合。 炎症反应和延迟愈合。伤口愈合受损的最新进展 是复杂的微生物群落（微生物组）存在于伤口组织内的知识。微生物 伤口组织中的细菌并不总是引起临床感染，但据认为它们可能持续炎症， 进一步损害愈合途径和皮肤修复。大多数已发表的伤口微生物组研究 概述了分类组成，但目前还不清楚这些不同的微生物群落实际上如何相互作用 并影响宿主修复途径。因此，微生物对组织再生的影响程度仍然是 有待解决。皮肤本身是一个多样化的生态系统，含有有益的微生物共生体， 调节宿主免疫应答并防止病原体定植。我们和其他人已经证明， 慢性伤口微生物组主要包括与皮肤病原体共存的皮肤微生物， 环境生物。这一发现表明，通常由皮肤微生物群提供的益处可能 它也强调了我们对微生物如何相互作用的不完全理解， 塑造主人的健康。 拟议的研究计划将定义结构化微生物群落形成的过程， 伤口组织，并将确定这些物种间相互作用的分子机制， 社区.我们将使用我们开发的活的离体人类皮肤伤口模型来实现这一点， 直接监测多物种联合体的生长动态和驻留皮肤细胞的免疫应答。我们 然后可以确定伤口愈合途径如何根据社区的组成而变化， 表型性状，如微生物生物膜的形成，在猪的伤口愈合模型。我们还将建立 根据我们最近的发现，健康皮肤微生物群的成员非常善于抑制 多种真菌的生长。当置于生态背景下时，这一发现并不奇怪，因为皮肤具有非常 真菌多样性低。然而，我们也表明，真菌定植和与细菌的相互作用是 与伤口组织坏死和延迟愈合显著相关。我们会分析代谢物 由健康皮肤微生物群介导与真菌的竞争性相互作用产生，并确定它们在 调节健康皮肤上和含有真菌的伤口微生物组内的微生物群落动态 和细菌密切互动。我们的研究将促进我们对受损伤口愈合的理解， 揭示微生物群落组装动态的基本过程。