Mechanism and Impact of Dermal adipocyte remodeling in skin fibrosis

真皮脂肪细胞重塑对皮肤纤维化的机制及影响

• 批准号: 10361445
• 负责人: RADHIKA P ATIT
• 金额: $ 48.2万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361445
• 关键词: Adipocytes; Adipose tissue; Aggressive Fibromatosis; Atopic Dermatitis; Biological Assay; Biology; Bleomycin; Cell Therapy; Cell physiology; Cells; Cessation of life; Chemical Models; Chemicals; Chronic; Cicatrix; Clinical; Collaborations; Data; Deposition; Dermal; Dermis; Development; Dipeptidases; Disease; Disease Progression; Europe; Event; Extracellular Matrix Proteins; Fatty Acids; Felis catus; Fibroblasts; Fibrosis; Generations; Genetic; Genetic Models; Genomics; Goals; Heart; Histologic; Human; Hypertrophic Cicatrix; Immunologics; Immunomodulators; In Vitro; Keloid; Kinetics; Laboratories; Lead; Lipase; Lipids; Lipodystrophy; Lipolysis; Lung; Modeling; Molecular; Mus; Organ; Participant; Pathologic; Pathway interactions; Patients; Process; Production; Profibrotic signal; Proteomics; Repression; Role; Scleroderma; Sclerosis; Signal Pathway; Signal Transduction; Skin; Stimulus; Testing; Therapeutic Intervention; Tissues; WNT Signaling Pathway; Work; adipocyte biology; base; cell type; chemical genetics; cytokine; dietary; efficacious treatment; experimental study; healing; human disease; improved; in vivo; in vivo Model; indium-bleomycin; insight; lipidomics; mouse model; new therapeutic target; novel; personalized medicine; prevent; regenerative therapy; response; single-cell RNA sequencing; skin fibrosis; skin organogenesis; therapeutic target; uptake

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.

总结 慢性纤维化是包括患者皮肤在内的许多器官中的各种疾病的病理标志 全身性和局限性硬化症、侵袭性纤维瘤病、瘢痕疙瘩、增生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意想不到的有趣作用： 抑制ECM的产生。特别是，我们发现成熟的脂肪细胞经历脂解以释放 脂肪酸在Wnt依赖性机制中起重要作用，脂肪细胞脂解具有纤维保护作用。我们的研究结果是 重要的原因有几个。首先，脂肪细胞已被证明可以改善疤痕，但如何成熟的脂肪细胞 在这个过程中的作用还不清楚。其次，脂肪组织损失是皮肤中的主要临床问题，并且是皮肤损伤的早期症状。 在皮肤纤维化的发展过程中。此外，脂肪细胞及其衍生物（脂肪酸和/或脂肪酸盐）也可用于治疗癌症。 细胞因子）是一种易处理的细胞类型，用于产生个性化治疗以促进纤维化患者的愈合。 通过两个重点突出和互补的具体目标，本申请中提出的工作将 允许特异性消除脂肪细胞脂解和纤维化的多种遗传小鼠模型的优点 开发、脂质组学和成纤维细胞培养测定，以确定皮肤过程中脂肪细胞脂解的功能 纤维化我们的目标是测试是否：1。脂肪细胞衍生的脂肪酸消除纤维化期间ECM的产生 发展;以及2. wnt刺激真皮脂肪细胞的脂解。为了实现这些目标，在Aim 1中，我们将定义 脂肪分解改变小鼠皮肤的细胞和分子变化，以及真皮脂肪细胞脂质是否可以 消除小鼠和人纤维化成纤维细胞或其它细胞类型中的纤维化反应。在Aim 2中，我们将测试 Wnts及其新候选效应子二肽基二肽酶4在刺激化学和 体内和体外遗传模型。这些研究的结果将为真皮脂肪细胞来源的 脂肪酸和Wnt信号传导靶点作为慢性皮肤纤维化及相关疾病的新治疗靶点 脂肪营养不良 影响：我们建议研究脂肪细胞脂质的功能和Wnt信号诱导的脂解作用， 皮肤纤维化这些结果将揭示新的细胞类型和分子途径参与脂质耗竭 这可能是纤维化发展和逆转的关键调节因子。这些实验的结果将阐明 皮内脂肪细胞和脂解作为新的参与者的贡献，并将通过开放改变该领域， 新的研究方向和治疗目标