Determining Host-microbiome guided oro-nasal fistula healing

确定宿主微生物组引导口鼻瘘愈合

• 批准号: 10545072
• 负责人: Steven L Goudy
• 金额: $ 19.52万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545072
• 关键词: Address; Affect; Antibiotics; Bacteria; Biopsy; Body Surface; Cells; Child; Cleft Palate; Communication; Communities; Craniofacial Abnormalities; Data; Development; Eating; Enterococcus faecalis; Environmental Risk Factor; Event; Exogenous Factors; Fistula; Gene Expression; Genes; Germ-Free; Gut Mucosa; HIV Infections; Homeostasis; Human; Hydrogels; Immune; Impairment; Innovative Therapy; Intestines; Knowledge; Live Birth; Low Prevalence; Measures; Metagenomics; Microbe; Mission; Modality; Modeling; Molecular; Mucous Membrane; Mus; Nasal cavity; Nose; Operative Surgical Procedures; Oral; Oral Surgical Procedures; Oral cavity; Patients; Population; Preparation; Prions; Probiotics; Process; Public Health; Regulator Genes; Research; Science; Signal Pathway; Signal Transduction; Site; Skin; Speech; Structure; Surgeon; Surgical wound; Technology; Testing; Tissue Donors; Tissues; Transcript; United States National Institutes of Health; commensal bacteria; congenital anomaly; craniofacial; disorder risk; experimental study; feeding; gene network; healing; host microbiome; improved; infection risk; intestinal injury; microbial community; microbiome; microbiome analysis; microbiome composition; microbiota; mouse model; novel therapeutic intervention; novel therapeutics; oral commensal; oral microbiome; palate repair; prevent; probiotic supplementation; recruit; regenerative; regenerative therapy; repaired; transcriptome sequencing; wound; wound bed; wound care; wound healing

SUMMARY Cleft palate formation is one of the most common craniofacial anomalies in children and occurs in 1:1000 live births. Patients undergo multiple surgeries during their lifetime and, for many, the first surgery is the repair of their cleft palate. However, 60% of cleft palate patients suffer poor wound healing following surgery which leads to the development of an oro-nasal fistula (ONF) characterized by a continued communication between the oral and nasal cavities. The primary approach to repair an ONF is by using human donor tissue, which acts only as a physical barrier and carries the risks of disease associated with human donor tissue, such as prions or HIV infection. Therefore, there is an urgent need to develop new therapeutic strategies to improve wound healing after cleft palate surgical repair, and to reduce the cases of ONF. Wound healing has been studied extensively on the skin and particularly following intestinal injury. Intestinal wound healing efficiency is highly sensitive to environmental factors, especially the microbiome, where specific microbial community structures or supplementation with probiotic bacteria enhances the wound healing process. However, little is known about how the oral microbiome affects ONF wound healing. We directly address this gap in the knowledge and show preliminary data that creating an ONF in a murine model results in marked changes in the microbiome composition, with the complete disappearance of certain microbes, and blooms of other bacterial taxa. Based on this premise, in Aim 1, we will create ONF wounds in germ-free mice, or in conventionally raised mice treated with antibiotics, and assess healing rates and changes in the oral microbiome composition. We expect to show the influence of disrupting the oral microbiome on healing processes and ONF formation. In Aim 2, we will use a hydrogel to re-introduce commensal oral microbes lost following surgery to the site of the oral wound and assess healing rates. We expect to show that repletion of oral commensal bacteria to the wound site can promote wound healing processes. In addition, by assessing transcript enrichment by RNA-seq within ONFs in germ-free, antibiotic treated mice, and after the repletion of oral commensal bacteria, we expect to identify gene networks that function in healing within ONFs that are sensitive to the commensal oral microbiome. Thus, our overall hypothesis is that the oral commensal microbiome exerts positive modulatory influences on oral wound healing and may limit ONF formation. Discovering specific bacterial taxa within the oral cavity or wound tissue that positively influence healing will be essential information for the characterization of an eubiotic oral microbiome for wound healing. Our experiments will also generate critical information for clinicians about the prudent use of antibiotics after cleft palate surgery and the effects of depleting the oral microbiome during healing. We will also substantiate the approach of the repletion of the oral commensal bacteria using hydrogel technology as the vehicle to enhance oral wound healing. Together, these studies will yield critical data to inform new therapeutic modalities to lower the prevalence of ONFs following cleft palate surgery.

概括 left裂的形成是儿童中最常见的颅面异常之一，发生在1：1000 Live 出生。患者在一生中接受了多次手术，在许多人中，第一次手术是修复 他们的口感。然而，手术后有60％ 导致开发Oro-Nasal瘘（ONF），其特征是 口腔和鼻腔。修复ONF的主要方法是使用人体供体组织 仅作为物理障碍，并承担与人类供体组织相关的疾病的风险 或HIV感染。因此，迫切需要制定新的治疗策略来改善伤口 left裂后的手术修复后进行愈合，并减少ONF的病例。伤口愈合已被研究 在皮肤上广泛，尤其是在肠道损伤之后。肠道伤口愈合效率高度高 对环境因素敏感，尤其是微生物组，特定的微生物社区结构或 补充益生菌可增强伤口愈合过程。但是，对 口服微生物组如何影响ONF伤口愈合。我们直接解决了知识和展示的差距 在鼠模型中创建ONF的初步数据导致微生物组的明显变化 成分，某些微生物完全消失，其他细菌分类单元的开花。基于 在此前提下，在AIM 1中，我们将在无细菌的小鼠或常规饲养的老鼠中产生ONF伤口 用抗生素处理，并评估口服微生物组组成的愈合率和变化。我们期望 显示破坏口服微生物组对愈合过程和ONF形成的影响。在AIM 2中，我们 将使用水凝胶将手术后的共性口服微生物重新引入口腔伤口。 并评估康复率。我们期望表明口腔共生细菌的补充可以 促进伤口愈合过程。另外，通过评估RNA-Seq在ONF中的成绩单富集 无菌，抗生素治疗的小鼠，口服共生细菌充满 对共生口服微生物组敏感的ONF内愈合中起作用的基因网络。因此， 我们的总体假设是口头共生微生物组对口服产生积极的调节影响 伤口愈合并可能限制ONF形成。在口腔或伤口中发现特定的细菌分类单元 积极影响愈合的组织将是表征口服的重要信息 微生物组可用于伤口愈合。我们的实验还将为临床医生生成关键信息 left裂手术后谨慎使用抗生素以及在耗尽口服微生物组的影响 康复。我们还将证实使用水凝胶的口腔共生细菌的补充方法 技术作为增强口腔伤口愈合的工具。这些研究将共同​​产生关键数据 告知新的治疗方式，以降低left裂手术后的ONF的患病率。