Mechanism and Impact of Dermal adipocyte remodeling in skin fibrosis

摘要 慢性纤维化是包括患者皮肤在内的许多器官疾病的病理特征。 全身性和局限性硬化症、侵袭性纤维瘤病、瘢痕疙瘩、肥厚性瘢痕和特应性皮炎。 我们的实验室最近发现了成熟脂肪细胞在皮肤纤维化过程中一个意想不到的有趣角色： 对ECM生产的压制。特别是，我们发现成熟的脂肪细胞经历脂肪分解释放。 脂肪酸在Wnt依赖的机制中，脂肪细胞脂解是纤维保护作用。我们的发现是 这很重要，有几个原因。首先，脂肪细胞已被证明可以改善疤痕形成，但脂肪细胞的成熟程度尚不清楚。 这一过程中的作用尚不清楚。其次，脂肪组织丢失是皮肤和早期的一个主要临床问题。 在皮肤纤维化的发展过程中的事件。此外，脂肪细胞及其衍生物(脂肪酸和/或 细胞因子)是一种易于处理的细胞类型，可创建个性化治疗，促进纤维化患者的愈合。 通过两个集中和互补的具体目标，本申请中提出的工作将采取 允许特异性消除脂肪细胞脂解和纤维化的多基因小鼠模型的优势 开发、脂质组学和成纤维细胞培养试验确定脂肪细胞脂肪分解在皮肤中的功能 纤维化症。我们的目标是测试：1.脂肪细胞衍生的脂肪酸是否能在纤维化过程中消除细胞外基质的产生 WNTS刺激真皮脂肪细胞的脂解作用。为了实现这些目标，在第一个目标中，我们将明确 脂肪分解改变小鼠皮肤的细胞和分子变化，如果真皮脂肪细胞脂可以 消除小鼠和人成纤维细胞或其他细胞类型的纤维化反应。在AIM2中，我们将测试 WNTS及其新的候选效应物二肽基二肽酶4在刺激化学和免疫系统中的脂解作用 体内和体外的遗传模型。这些研究的结果将为真皮脂肪细胞来源的 脂肪酸和Wnt信号转导靶点作为慢性皮肤纤维化及其相关治疗的新靶点 脂肪营养不良。 影响：我们建议在以下情况下研究脂肪细胞脂质和Wnt信号诱导的脂解作用 皮肤纤维化。这些结果将揭示与脂质耗竭有关的新的细胞类型和分子途径 这可能是纤维化发展和逆转的关键调节因素。这些实验的结果将阐明 皮内脂肪细胞和脂肪分解作为新参与者的贡献，并将通过开放改变这一领域 新的调查路线和治疗目标。

Summary Chronic fibrosis is the pathological hallmark in a variety of disorders in many organs including the skin in patients with systemic and limited sclerosis, aggressive fibromatoses, keloid, hypertrophic scarring, and atopic dermatitis. Our laboratories recently uncovered an unexpected and intriguing role for mature adipocytes during skin fibrosis: repression of ECM production. In particular, we identified that mature adipocytes undergo lipolysis to release fatty acids in a Wnt-dependent mechanism and that adipocyte lipolysis is fibroprotective. Our findings are important for several reasons. First, adipocytes have been shown to improve scarring yet how mature adipocytes function in this process is unclear. Second, adipose tissue loss is a major clinical issue in the skin and an early event in the development of skin fibrosis. Furthermore, adipocytes and their derivatives (fatty acids and/or cytokines) are a tractable cell type to create a personalized therapy to promote healing in patients with fibrosis. Through two focused and complementary Specific Aims, the work proposed in this application will take advantage of multiple genetic mouse models that allow specific abrogation of adipocyte lipolysis and fibrosis development, lipidomics, and fibroblast culture assays to define the function of adipocyte lipolysis during skin fibrosis. Our goals are to test whether: 1. adipocyte-derived fatty acids abrogate ECM production during fibrosis development; and 2. Wnts stimulate lipolysis of dermal adipocytes. Towards these goals, in Aim1, we will define the cellular and molecular changes by which lipolysis alters mouse skin and if dermal adipocyte lipids can abrogate the fibrotic response in mouse and human fibrotic fibroblasts or other cell types. In Aim2, we will test the role of Wnts and its new candidate effector, Dipeptidyl dipeptidase 4 in stimulating lipolysis in chemical and genetic models in vivo and in vitro. Results from these studies will provide a role for dermal adipocyte derived fatty acids and Wnt signaling targets as new therapeutic targets in chronic skin fibrosis and associated lipodystrophy. Impact: We propose to study the function of adipocyte lipids and Wnt signaling induced lipolysis in context of dermal fibrosis. These results will reveal novel cell types and molecular pathways involved in lipid depletion that can be a key regulator of fibrosis development and reversal. Results from these experiments will elucidate the contribution of intradermal adipocytes and lipolysis as new participants and will change the field by opening new lines of inquiry and therapeutic targets.