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

项目摘要 口腔代表着一个相对未被开发的独特的愈合环境。在网络中再生 口腔粘膜发生迅速，伤口闭合的速度是皮肤的四倍，并且会出现炎症反应 对伤人的打击相对较小。口腔内的慢性伤口损害了患者的能力 儿童需要获取营养，容易受到致衰性感染，因此构成了一个重要的口腔健康问题。 了解口腔粘膜是如何实现这种再生的，因此了解伤口愈合是如何进行的 在疾病环境中被破坏，将是颅面研究领域的一项重大成就。这个 口腔粘膜用来促进其独特再生表型的特定细胞机制仍然存在 难以捉摸，并在本提案中得到解决。 比较真皮和口腔伤口的研究表明，口腔伤口愈合时间较短 炎症阶段，随后通过上皮细胞的增殖、迁移迅速过渡到伤口闭合 和差异化。口腔慢性炎症是许多疾病的原因，如牙周炎， 口腔粘膜炎和颌骨坏死，但炎症如何导致上皮萎缩或挥之不去的开放 口腔粘膜中的伤口尚不清楚。鉴于口腔上皮祖细胞(OEPC)数量在 重新上皮化，这一建议将检验炎症作为一种重要的协调者的假说。 通过直接调节OEPC数量，伤口闭合和再上皮化。伤口愈合将是 在三种炎症状态下对动物进行评估：正常、低和高。衰减和衰减的影响 再生时炎症加重将通过伤口闭合时间评分来确定，上皮 整个组织内的层完整性、增殖和凋亡(目标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 三种条件下的测序，以及免疫系统对上皮细胞的直接调节 使用体外共培养系统(目标2)。来自这些目标的数据将决定炎症如何调节 伤口闭合，阐明炎症影响再上皮化的关键机制， 将为口腔粘膜内伤口闭合的机制提供有价值的见解。 这些研究目标将与一项全面的培训计划一起进行，旨在 发展申请者作为牙医科学家的职业生涯。培训包括来自两个高度 合格的临床医生-科学家赞助人，通过个人和小组会议进行科学技术培训， 研讨会、杂志俱乐部、课程和部门活动。研究和培训将在该大学进行 加利福尼亚州的旧金山，它提供了出色的研究环境和出色的牙科 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.