An immunomodulatory approach to improve oral cavity wound healing

改善口腔伤口愈合的免疫调节方法

• 批准号: 9974156
• 负责人: Steven L Goudy
• 金额: $ 56.18万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9974156
• 关键词: Affect; Agonist; Allografting; Area; Bacteria; Biocompatible Materials; Biological Assay; Blood; Cells; Child; Chronic; Cleft Palate; Clinical Trials; Craniofacial Abnormalities; Cytokine Gene; Data; Dermal; Development; Dimensions; Drug Delivery Systems; Drug Targeting; Eating; Engineering; Environment; FDA approved; Fistula; Future; Gene Expression; Genes; Genetic Models; Goals; HIV; Human; Immune; Immune response; Implant; Inflammatory; Inflammatory Response; Injury; Innovative Therapy; Live Birth; Mission; Modeling; Morbidity - disease rate; Mucous Membrane; Multiple Sclerosis; Mus; Muscle; Operative Surgical Procedures; Oral; Oral cavity; Palate; Paper; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenocopy; Population; Prions; Process; Production; Public Health; Publishing; Research; Risk; Role; Science; Signal Transduction; Skin; Skin wound healing; Soft Tissue Injuries; Speech; Sphingosine; Sphingosine-1-Phosphate Receptor; Surgeon; Surgical Flaps; System; Testing; Time; Tissue Donors; Tissue Engineering; Tongue; Trauma; United States National Institutes of Health; base; cell motility; congenital anomaly; cost; craniofacial; cytokine; feeding; healing; immunomodulatory strategy; immunomodulatory therapies; immunoregulation; improved; infection risk; injured; innovation; macrophage; migration; monocyte; mouse genetics; mouse model; nanofiber; novel; palate repair; prevent; progenitor; programs; reconstruction; recruit; regenerative; regenerative therapy; repaired; response; response to injury; scaffold; single-cell RNA sequencing; small molecule; soft tissue; targeted treatment; therapeutic target; therapy outcome; tissue regeneration; tool; transcriptome sequencing; transmission process; treatment optimization; wound bed; wound healing

PROJECT SUMMARY: Cleft palate patients (1:1000 live births) all undergo palate repair; however, 60% de- velop complications including oronasal fistula (ONF) formation. ONF formation leads to poor feeding and speech. Cleft palate repair involves rotating palate mucosal flaps into the cleft and healing is affected by physi- cal trauma from the tongue and a bacteria laden environment. Currently, cleft palate repair surgeries lack a regenerative reconstructive option, require multiple re-repairs due to ONF and increase cost and morbidity. Surgeons use allograft dermal implants, despite the risk of HIV/prion transmission, to act solely as a barrier to reduce ONF. Our group has developed a novel murine phenocopy of ONF, and identified a unique immuno- modulatory approach to directing the ONF healing process in a pro-regenerative program. FTY720, an active biolipid, targets the sphingosine pathway to preferentially attract pro-regenerative monocytes and macrophag- es to improve ONF healing. Our long-term goal is to develop an immunoregenerative approach to improve pal- ate wound healing. The overall objective in this application is to determine the mechanism of ONF healing and use FTY720 nanofibers to tune the monocyte and macrophage migration in a pro-regenerative fashion. The central hypothesis is that inflammatory monocytes and macrophages are the predominant response during oral cavity wound healing and that delivery of FTY720 preferentially attracts pro-regenerative monocytes and mac- rophages leading to improved wound healing. FTY720 signals through the sphingosine pathway, increasing the recruitment of pro-regenerative monocytes and macrophages. The rationale for the proposed research is that a comprehensive and mechanistic understanding of the inflammatory response during ONF formation will provide therapeutic targets aimed at altering pro-regenerative monocyte migration. Guided by strong prelimi- nary data, including a paper demonstrating significant reduction in ONF following FTY720 nanofiber delivery, the hypothesis will be tested by pursuing two specific aims: 1) Determine the requirement, timing and mecha- nistic contributions of the inflammatory response during ONF formation; 2) Engineer a nanofiber scaffold to provide controlled delivery of FTY720 to improve oral cavity wound healing using an immunoregenerative ap- proach. In Aim 1 we will identify the critical inflammatory cell recruitment to healing ONF, determine the re- quirement of monocytes, and identify alteration in the cytokines and reparative gene pathways following ONF formation. In Aim 2, we will test the optimal FTY720 delivery strategy, the ability of FTY720 nanofiber to direct pro-regenerative ONF wound healing with and without monocytes, and determine the effects of FTY720 nano- fiber on the cytokines and reparative gene pathways. The proposed research is innovative by mechanistically describing monocyte migration in an ONF murine model that allows testing of immunomodulatory strategies. The proposed research is significant because it that FTY720, an FDA-approved drug approved to treat multiple sclerosis, could be fast tracked to clinical trials to reduce ONF formation.

项目摘要：a裂的患者（1：1000例出生）都接受了口感修复；但是，有60％ 天线并发症，包括Ororanasal瘘（ONF）形成。 ONF形成导致喂养不佳和 演讲。 left裂的修复涉及旋转口感粘膜瓣进入裂缝，愈合受到物理的影响 舌头和细菌充满活力的环境。目前，口腔修复手术缺乏 再生重建选项，由于ONF而需要多次重新替代，并提高了成本和发病率。 外科医生使用同种异体皮肤植入物，尽管有艾滋病毒/prion传播的风险，但仅充当障碍 减少ONF。我们的小组已经开发了一种新型的ONF鼠类表观，并确定了独特的免疫。 调节方法来指导ONF愈合过程中的促进程序。 fty720，活跃 Biolipid的靶向鞘氨醇途径，优先吸引促启发性单核细胞和巨噬细胞 - ES改善ONF愈合。我们的长期目标是开发一种免疫加快方法来改善PAL- 吃了伤口愈合。本应用程序的总体目的是确定ONF愈合的机制和 使用fty720纳米纤维以促进性的方式调整单核细胞和巨噬细胞迁移。这 中心假设是炎性单核细胞和巨噬细胞是口服期间的主要反应 空腔伤口愈合和FTY720的递送优先吸引促增再生的单核细胞和MAC- 导致伤口愈合的改善。 FTY720通过鞘氨醇途径发出信号，增加 促进再生单核细胞和巨噬细胞的募集。拟议研究的理由是 对ONF形成过程中炎症反应的全面和机械理解将 提供旨在改变促促再生单核细胞迁移的治疗靶标。在强大的前提下指导 NARY数据，包括一篇论文，表明FTY720纳米纤维传递后的ONF显着降低， 该假设将通过追求两个具体目的来检验：1）确定要求，时机和机甲 ONF形成过程中炎症反应的贡献； 2）工程师纳米纤维支架 提供受控递送FTY720，以改善口腔伤口愈合 proach。在AIM 1中，我们将确定关键的炎性细胞募集以恢复治疗，确定重新 单核细胞的问题，并鉴定ONF后细胞因子和修复基因途径的改变 形成。在AIM 2中，我们将测试最佳FTY720交付策略，即FTY720纳米纤维指导的能力 有或没有单核细胞的促增长ONF伤口愈合，并确定FTY720纳米的影响 细胞因子和修复基因途径的纤维。拟议的研究是通过机械机理创新的 在ONF鼠模型中描述单核细胞迁移，该模型允许测试免疫调节策略。 拟议的研究很重要，因为它是FTY720，一种经FDA批准的药物批准用于治疗多重的药物 硬化症可以快速跟踪到临床试验以减少ONF形成。