Characterization and Treatment of the Scarred Vocal Fold

描述（由申请人提供）：声带（VF）粘膜损伤导致瘢痕形成及其相关发声困难是一种使人衰弱且具有挑战性的临床问题，对此没有持续有效的治疗方法。VF瘢痕生物学中最不了解但可能具有变革性的研究领域之一是储存维生素A的VF星状细胞的作用。该细胞群位于黄斑前部和后部，是必需维生素A的局部储存库，并被假设在VF固有层内的发育、维持、损伤反应和瘢痕形成中发挥主要作用。其他器官中的星状细胞（例如，肝、胰腺和肺）是已知的纤维化的基本调节因子。在这些器官中，炎症刺激促进星状细胞活化，导致细胞质维生素A的损失，细胞外基质（ECM）合成增加，分化为收缩（肌成纤维细胞）表型，和瘢痕形成。新兴的研究，其中一些是在我们最近的资助周期中进行的，表明VF星状细胞经历了类似的激活过程，并且可能在VF粘膜损伤和瘢痕形成中具有类似的作用。我们的长期目标是明确表征VF星状细胞在F伤口愈合和瘢痕形成中的作用，以及视黄酸（生物活性维生素A）逆转VF星状细胞活化和减弱瘢痕形成的治疗潜力。该项目有三个具体目标。在目标1中，我们将进行动物实验并使用从人尸体采集的组织/血清来鉴定维生素A转运至VF星状细胞的机制，提供VF星状细胞维生素A储存的群体变异估计，并建立VF粘膜、肝脏和血清中维生素A储存之间的对应程度。在目标2中，我们将使用计算建模和体外细胞培养技术来研究生物力学，生化/细胞因子，ECM和细胞环境因素对VF星状细胞表型的影响，在损伤和非损伤条件下。在目标3中，我们将检查视黄酸（生物活性维生素A）在体外和体内拯救VF星状细胞免于活化/纤维化表型的能力。完成后，这个治疗驱动的项目将提供明确的定义表型差异之间 VF星状细胞、VF成纤维细胞和其他器官中的星状细胞揭示了在动物和人类中将全身性维生素A（和与维生素A缀合的其他治疗分子）递送至VF星状细胞的最佳方法，并量化了视黄酸通过将VF星状细胞恢复至其静止状态来减弱瘢痕形成的能力。视黄酸已被美国食品药品监督管理局批准用于临床，在其他器官系统中作为抗纤维化药物具有已证实的疗效，因此未来可用于VF粘膜损伤和瘢痕患者。

DESCRIPTION (provided by applicant): Vocal fold (VF) mucosal injury resulting in scar formation and its associated dysphonia is a debilitating and challenging clinical problem, for which there is no consistently effective treatment. One of the most poorly understood but potentially transformative areas of investigation in VF scar biology is the role of the vitamin A- storing VF stellate cell. Localized to the anterior and posterior macula flavae, this cell populatin is a local repository of essential vitamin A and has been hypothesized to play a primary role in development, maintenance, injury response and scar formation within the VF lamina propria. Stellate cells in other organs (e.g., liver, pancreas, and lung) are known fundamental regulators of fibrosis. In these organs, inflammatory stimuli promote stellate cell activation, leading to los of cytoplasmic vitamin A, increased extracellular matrix (ECM) synthesis, differentiation to a contractile (myofibroblast) phenotype, and scar formation. Emerging research, some of which was conducted during our most recent funding cycle, suggests that VF stellate cells undergo a similar activation process and may have a comparable role in VF mucosal injury and scar formation. Our long- term goal is to definitively characterize the role of the VF stellate cell in F wound healing and scar formation, as well as the therapeutic potential of retinoic acid (bioactive vitamin A) to reverse VF stellate cell activation and attenuate scar formation. The proposed project has three Specific Aims. In Aim 1, we will conduct animal experiments and use tissue/serum harvested from human cadavers to identify the mechanism(s) of vitamin A transport to VF stellate cells, provide an estimate of population variation in VF stellate cell vitamin A storage, and establish the degree of correspondence between vitamin A stores in VF mucosa, liver and serum. In Aim 2, we will use computational modeling and in vitro cell culture techniques to study the effects of biomechanical, biochemical/cytokine, ECM and cellular environmental factors on the VF stellate cell phenotype, under injury and non-injury conditions. In Aim 3, we will examine the ability of retinoic acid (bioactive vitamin A) to rescue VF stellate cells from an activated/fibrotic phenotype, in vitro and in vivo. On completion, this therapeutically- driven project will provide clear definition of the phenotypic differences between VF stellate cells, VF fibroblasts and stellate cells in other organs, reveal the best approach to deliver systemic vitamin A (and other therapeutic molecules conjugated to vitamin A) to VF stellate cells in both animals and humans, and quantify the ability of retinoic acid to attenuate scar formation by restoring VF stellate cells to their quiescent state. Retinoic acid is approved for clinical use by the United States Food and Drug Administration, holds demonstrated efficacy as an antifibrotic agent in other organ systems, and is therefore well-positioned for future translation to patients with VF mucosal injury and scar.