Deciphering Inflammatory Regulation of Oral Epithelial Progenitor Cells During Oral Mucosal Regeneration

项目摘要 口腔代表了一个独特的愈合环境，是相对未开发的。再生之内 口腔粘膜迅速发生，伤口以皮肤的四倍速度闭合，并且炎症反应 对创伤的反应相对受到抑制。口腔内的慢性伤口损害患者的能力， 缺乏营养，容易受到使人衰弱的感染，从而构成一个重要的口腔健康问题。 了解口腔粘膜如何能够实现这种再生，因此伤口愈合是如何 在疾病环境中被破坏，将是颅面研究领域的一项重大成就。的 口腔粘膜用于促进其独特再生表型的特定细胞机制仍然存在 这一点在本提案中得到了解决。 比较皮肤和口腔伤口的研究表明，口腔伤口愈合显示出短暂的 炎症阶段，随后通过上皮细胞增殖、迁移、 和差异化。口腔中的慢性炎症是许多病理的原因，例如牙周炎， 口腔粘膜炎和颌骨骨坏死，但炎症如何导致上皮萎缩或迟迟不开 口腔粘膜的伤口未知。鉴于口腔上皮祖细胞（OEPC）群体介导了 再上皮化，这一建议将测试炎症作为一个重要的协调者的假设， 通过直接调节OEPC群体实现伤口闭合和上皮再形成。伤口愈合将是 在三种炎症状态下评估动物：正常、低和高。减毒和 通过对伤口闭合时间、上皮细胞增殖时间和炎症反应时间进行评分， 层完整性以及整个组织内的增殖和凋亡（Aim 1）。接下来，细胞和分子 将使用单细胞RNA来确定对OEPC群体的炎症调节机制 在三种条件下进行测序，并通过测试的免疫系统直接调节上皮细胞 使用体外共培养系统（Aim 2）。来自这些目标的数据将确定炎症如何调节 伤口闭合并阐明炎症影响上皮再生的关键机制， 将对口腔粘膜内伤口闭合的机制产生有价值的见解。 这些研究目标将与一个全面的培训计划一起进行， 发展申请人作为牙医科学家的职业生涯。培训包括来自两个高度专业的 合格的临床医生-科学家赞助人，以及通过个人和小组会议进行的科学和技术培训， 研讨会、期刊俱乐部、课程和部门活动。研究和培训将在该大学进行 位于加州的旧金山弗朗西斯科，提供了一个出色的研究环境和一个优秀的牙科 临床培训学校

Project Summary The oral cavity represents a unique healing environment that is relatively unexplored. Regeneration within the oral mucosa occurs rapidly, with wounds closing at four times the rate of the skin, and the inflammatory reaction to wounding is relatively suppressed. Chronic wounds within the oral cavity compromise the ability of patients to obtain nutrition and are prone to debilitating infections, thus constituting an important oral health problem. Understanding how the oral mucosa is able to achieve such regeneration, and therefore how wound healing is disrupted in disease environments, would be a significant achievement for the field of craniofacial research. The specific cellular mechanisms used by the oral mucosa to facilitate its distinct regenerative phenotype remain elusive and are addressed in this proposal. Studies comparing dermal and oral wounds have shown that oral wound healing displays a short inflammatory phase followed by a rapid transition into wound closure via epithelial cell proliferation, migration and differentiation. Chronic inflammation in the oral cavity is the cause of many pathologies, such as periodontitis, oral mucositis and osteonecrosis of the jaw, but how inflammation leads to epithelial atrophy or lingering open wounds in the oral mucosa is unknown. Given that the oral epithelial progenitor cell (OEPC) population mediates re-epithelialization, this proposal will test the hypothesis that inflammation acts as an important coordinator of wound closure and re-epithelialization via direct regulation of the OEPC population. Wound healing will be assessed in animals under three inflammatory states: normal, low and high. The effects of attenuated and exacerbated inflammation on regeneration will be established by scoring for time to wound closure, epithelial layer integrity and proliferation and apoptosis within the entire tissue (Aim 1). Next, the cellular and molecular mechanisms of inflammatory regulation on the OEPC population will be determined using single cell RNA sequencing under the three conditions, and direct regulation of the epithelium by the immune system tested using an in vitro co-culture system (Aim 2). Data from these aims will determine how inflammation regulates wound closure and elucidate key mechanisms through which inflammation influences re-epithelialization, which will yield valuable insights into the mechanisms of wound closure within the oral mucosa. These research goals will be conducted in conjunction with a comprehensive training plan designed to develop the applicant’s career as a dentist-scientist. The training includes structured mentorship from two highly qualified clinician-scientist sponsors, and scientific and technical training through individual and group meetings, seminars, journal clubs, classes and departmental events. Research and training will take place at the University of California, San Francisco, which offers both an outstanding research environment and an excellent dental school for clinical training.