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

项目摘要 我的研究计划的目标是了解微生物群落如何 在伤口组织中聚集，以及这些群落如何影响皮肤中的组织修复途径。在.期间 正常的伤口愈合，导致组织再生的过程是一系列严格调控的结果 连续事件。对于慢性的、无法愈合的伤口，这一过程被打乱，导致长期的 炎症反应和愈合停滞。创面愈合受损理解的关键新进展 是知道伤口组织中存在复杂的微生物群落(微生物群)。微生物群 在伤口组织中并不总是会引起临床感染，但人们认为它们可能会持续炎症， 进一步损害愈合途径和皮肤修复。在所有已发表的伤口微生物组研究中， 描述分类组成，但不清楚这些不同的微生物群落实际上是如何相互作用的 具有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存在。 有待解决。皮肤本身是一个多样化的生态系统，其中含有有益的微生物共生体，这些共生体的功能是 调节宿主免疫反应，防止病原体定植。我们和其他人已经证明了 慢性创面微生物群主要由与皮肤病原体共存的皮肤共生菌和 环境有机体。这一发现表明，通常由皮肤微生物区系赋予的益处可能 在创伤环境中迷失，这也突显了我们对微生物如何相互作用的不完全理解 塑造宿主健康。 拟议的研究计划将定义结构化微生物群落形成的过程 并将确定支配这些组织内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体体外人类皮肤创伤模型来实现这一点 直接监测多物种联合体的生长动态和常驻皮肤细胞的免疫反应。我们 然后可以确定伤口愈合路径如何随着社区的组成和 在猪伤口愈合模型中的表型特征，如微生物生物膜的形成。我们还将建立 根据我们最近的发现，健康皮肤微生物区系的成员非常擅长抑制 各种真菌的生长。当放在生态环境中时，这一发现并不令人惊讶，因为皮肤非常 真菌多样性低。然而，我们也证明了真菌的定植和与细菌的相互作用 与伤口组织坏死和延迟愈合显著相关。我们将对这些代谢物进行表征 由健康的皮肤微生物区系产生，介导与真菌的竞争性相互作用，并确定它们在 调节健康皮肤和含有真菌的伤口内微生物群落的动态 与细菌密切互动。我们的研究将促进我们对受损的伤口愈合和意志的理解 揭示控制微生物群落组装动力学的基本过程。

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.