An immunomodulatory approach to improve oral cavity wound healing

改善口腔伤口愈合的免疫调节方法

基本信息

批准号：
10371914
负责人：
Steven L Goudy
金额：
$ 54.12万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/10371914
关键词：
Affect Agonist Allografting Area Bacteria Biocompatible Materials 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 Morbidity - disease rate Mucous Membrane Multiple Sclerosis Mus Muscle Nanofiber Scaffold 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 efficacy evaluation feeding healing immunomodulatory strategy immunomodulatory therapies immunoregulation improved infection risk injured innovation macrophage migration monocyte mouse genetics mouse model multiplex assay nanofiber novel palate repair prevent progenitor programs reconstruction recruit regenerative regenerative therapy repair model 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

项目摘要

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.

项目概要：腭裂患者（1:1000活产）全部接受腭修复；然而，60% 并发症包括口鼻瘘（ONF）形成。 ONF 的形成导致喂养不良和演讲。腭裂修复涉及将腭粘膜瓣旋转到裂口中，愈合受到物理影响。来自舌头的创伤和充满细菌的环境。目前，腭裂修复手术缺乏再生重建选项，由于 ONF 需要多次重新修复，并增加成本和发病率。尽管存在艾滋病毒/朊病毒传播的风险，外科医生仍使用同种异体真皮植入物，仅作为屏障减少ONF。我们的小组开发了一种新型的 ONF 小鼠表型，并鉴定了一种独特的免疫- 在促再生程序中指导 ONF 愈合过程的调节方法。 FTY720，主动生物脂质，靶向鞘氨醇途径，优先吸引促再生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再生方法来改善皮肤吃了伤口愈合。本申请的总体目标是确定 ONF 愈合的机制和使用 FTY720 纳米纤维以促再生方式调节单核细胞和巨噬细胞迁移。这中心假设是炎症性单核细胞和巨噬细胞是口腔过程中的主要反应。 FTY720 的递送优先吸引促再生单核细胞和 Mac- 噬菌体可改善伤口愈合。 FTY720 通过鞘氨醇途径发出信号，增加募集促再生单核细胞和巨噬细胞。拟议研究的理由是对 ONF 形成过程中炎症反应的全面和机制的了解将有助于提供旨在改变促再生单核细胞迁移的治疗靶点。在强有力的预先指导下多项数据，包括一篇论文，证明 FTY720 纳米纤维输送后 ONF 显着减少，该假设将通过追求两个具体目标来检验：1）确定要求、时间安排和机制 ONF形成过程中炎症反应的本质贡献； 2）设计纳米纤维支架使用免疫再生应用提供 FTY720 的受控递送以改善口腔伤口愈合传道。在目标 1 中，我们将确定愈合 ONF 的关键炎症细胞募集，确定重新单核细胞的询问，并识别 ONF 后细胞因子和修复基因途径的变化形成。在目标 2 中，我们将测试最佳 FTY720 递送策略，即 FTY720 纳米纤维引导的能力使用和不使用单核细胞的促再生 ONF 伤口愈合，并确定 FTY720 纳米的效果纤维对细胞因子和修复基因途径的影响。所提出的研究在机械上具有创新性描述了 ONF 小鼠模型中的单核细胞迁移，该模型允许测试免疫调节策略。拟议的研究意义重大，因为 FTY720 是 FDA 批准的一种药物，被批准用于治疗多种疾病硬化症，可以快速进入临床试验，以减少 ONF 的形成。