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

项目摘要/摘要 对于像我这样的儿科妇科医生来说，手术后纤维化的高发病率不是一项微不足道的壮举 在为数不多的接受过复杂的阴道重建手术培训的专家中。令人震惊的是 令人困惑的是，与真皮组织不同的是，口腔、胃肠道和阴道粘膜的程序是可以愈合的 可再生且无疤痕。然而，没有科学地量身定做的临床策略来预防或治疗 最少治疗阴道纤维化，目前依赖于应用带有基本扩张器的组织拉伸或 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， 青少年和成年女性患者的医疗费用增加，生活质量显著下降 刚刚经历了阴道手术、受伤或骨盆放射的创伤。我计划用这个K08奖来 将自己发展为少数儿科妇科外科医生-科学家之一，并利用这个平台了解 是什么引导阴道粘膜组织进入再生或纤维化修复。虽然我承认 知识，我也认识到，破解组织再生和纤维化的二分法的关键在于 无处不在的细胞外基质(ECM)信号，特别是通过蛋白多糖，如透明质酸通过 一种特定的受体。特别是，透明质酸(HA)通过其高亲和力影响伤口愈合 受体CD44，后者在HA结合时参与炎症反应。值得注意的是，支持- 炎性低分子量和抗炎高分子量(LMW/HMW)HA变体合成于 损伤，这导致我质疑雌激素水平是否在调节ECM如何引导HA/CD44方面发挥作用 阴道粘膜中的信号。值得注意的是，我的初步数据显示，纤维化可以通过 雌激素和透明质酸(HA)联合控释，其中联合保护作用 通过增强抗炎和促血管生成反应来支持抗纤维化。通过测试 不同材料特性的支架，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体。 然而，缺少的一环是，将雌激素驱动的HA/CD44信号转导到 粘膜修复尚不清楚。因此，我的首要假设是阴道伤口的方向 修复是由雌激素驱动的信号通过HA配体/CD44受体相互作用转导的 对紧张做出反应。因此，我的目标是：(I)研究雌激素在阴道HA生物学调节中的作用 组织修复；(Ii)研究雌激素如何驱动CD44信号介导的阴道炎症及其影响 再生组织修复；以及(Iii)测试调节雌激素-HA轴是否可以促进伤口修复。在… 这次K08大奖结束后，我将获得必要的技能和知识，成为一名独立的 研究人员，追求外科医生兼科学家的职业生涯，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.