Hormones and Mechanotherapeutics: Restoring Altered Hyaluronan Biology in Mucosal Wound Healing Using Vaginal Tissue as a Model

项目总结/摘要 术后纤维化的高发病率对于像我这样的儿科妇科医生来说不是一件小事， 是少数接受过复杂阴道重建手术培训的专家之一。令人震惊的是 令人困惑的是，与皮肤组织不同，口腔、胃肠道和阴道粘膜的愈合是有程序的 再生，不留疤痕。然而，目前还没有科学的临床策略来预防或 最少治疗阴道纤维化，目前依赖于使用基本扩张器进行组织拉伸， 支架和手术前后雌激素的局部治疗。不可避免的结果是高发病率， 卫生保健费用增加，青少年和成年女性患者的生活质量显著下降 刚刚经历了阴道手术、受伤或盆腔放射的创伤。我打算用这个K 08奖 发展自己作为少数几个儿科妇科外科医生科学家之一，并利用这个平台来了解 引导阴道粘膜组织进行再生或纤维化修复。虽然我承认我们之间的差距 知识，我也认识到，破译组织再生和纤维化二分法的关键在于 普遍存在的细胞外基质（ECM）信号传导，特别是通过蛋白聚糖如透明质酸， 一种特殊的受体具体地，已知透明质酸（HA）通过其高亲和力影响伤口愈合。 受体CD 44，其中后者在HA结合后参与炎症反应。值得注意的是，亲- 炎症性低分子量和抗炎性高分子量（LMW/HMW）HA变体是在以下条件下合成的： 损伤，这使我质疑雌激素水平是否在调节ECM如何引导HA/CD 44方面发挥任何作用 阴道粘膜中的信号。值得注意的是，我的初步数据表明，纤维化可以减弱， 联合雌激素和透明质酸（HA）控释递送，其中联合的保护作用 通过增强的抗炎和促血管生成反应来支持抗纤维化。通过测试 这些研究还揭示了组织拉伸的临界阈值， 有助于再生修复，并表明HA和雌激素是这些作用的重要介质。 然而，缺少的环节是雌激素驱动的HA/CD 44信号传导的机制， 粘膜修复仍然未知。因此，我的首要假设是阴道伤口的方向 修复受雌激素驱动的信号控制，这些信号通过HA配体/CD 44受体相互作用转导， 应对紧张。因此，我的目的是：（i）研究雌激素对阴道HA生物学的调节作用， 组织修复;（ii）研究雌激素如何驱动CD 44信号介导的阴道炎症， 再生组织修复;和（iii）测试调节雌激素-HA轴是否可以改善伤口修复。在 在这个K 08奖结束时，我将获得必要的技能和知识，成为一个独立的 研究员，追求外科医生科学家的职业生涯，并领导粘膜再生领域。

Project Summary/Abstract The high incidence of post-surgical fibrosis is no trivial feat for a pediatric gynecologist such as myself who is among the the few specialists trained to perform intricate vaginal reconstruction surgeries. What is strikingly perplexing is that, unlike dermal tissues, oral, gastrointestinal, and vaginal mucosa are programmed to heal regeneratively and without scarring. Yet, there are no scientifically tailored clinical strategies to prevent or at least treat vaginal fibrosis, which currently rely on the application of tissue stretch with rudimentary dilators or stents and local treatment with pre- and post-operative estrogen. The inevitable result is high morbidity, increased health care costs, and significant reduction in quality of life for adolescent and adult female patients that had just endured the trauma of vaginal surgery, injury, or pelvic radiation. I plan to use this K08 award to develop myself as one of a few pediatric gynecological surgeon-scientists and use this platform to understand what directs vaginal mucosal tissue into regenerative or fibrotic repair. While I acknowledge the gap of knowledge, I also recognize that the key to decipher the dichotomy of tissue regeneration and fibrosis lies with the ubiquitous extracellular matrix (ECM) signaling, particularly through proteoglycans such as hyaluronan via a specific receptor. In particular, hyaluronan (HA) is known to impact wound healing through its high affinity receptor CD44, where the latter engages in inflammatory reactions upon HA binding. Remarkably, pro- inflammatory low and anti-inflammatory high molecular weight (LMW/HMW) HA variants are synthesized upon injury, which led me to query whether estrogen levels play any role to modulate how ECM directs HA/CD44 signaling in the vaginal mucosa. Notably, my preliminary data show that fibrosis can be attenuated by combined estrogen and hyaluronan (HA) controlled release delivery, where the combined protective effect against fibrosis was upheld by enhanced anti-inflammatory and pro-angiogenic reactions. Through testing of stents with different material properties, these studies also unveiled a critical threshold of tissue stretch that contributes to regenerative repair and suggest that HA and estrogen are essential mediators of these effects. However, the missing link is that the mechanisms that transduce estrogen-driven HA/CD44 signaling to direct mucosal repair remain unknown. Hence, my overarching hypothesis is that the direction of vaginal wound repair is governed by estrogen-driven signals transduced via HA ligand/CD44 receptor interactions that respond to tension. Thus, I aim to: (i) Investigate the role of estrogen on the regulation of HA biology in vaginal tissue repair; (ii) Study how estrogen drives CD44 signaling-mediated vaginal inflammation and influences regenerative tissue repair; and (iii) Test whether regulating the estrogen-HA-axis can improve wound repair. At the end of this K08 award, I will have acquired the necessary skills and knowledge to become an independent investigator, pursue a career as a surgeon-scientist, and lead the field of mucosal regeneration.