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

基本信息

批准号：
9917422
负责人：
RADHIKA P ATIT
金额：
$ 51.76万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/9917422
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 Diet 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 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 experimental study healing human disease improved in vivo in vivo Model indium-bleomycin insight mouse model new therapeutic target novel personalized medicine prevent regenerative therapy response single-cell RNA sequencing skin fibrosis skin organogenesis therapeutic target uptake

项目摘要

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.

概括慢性纤维化是许多器官中多种疾病的病理标志，包括患者的皮肤具有全身性和有限的硬化症，侵袭性纤维瘤，乳腺癌，肥厚性疤痕和特应性皮炎。我们的实验室最近发现了皮肤纤维化期间成熟脂肪细胞的意外和有趣的作用：抑制ECM生产。特别是，我们确定成熟的脂肪细胞经历脂肪分解以释放 Wnt依赖性机制中的脂肪酸和脂肪细胞脂解具有纤维化保护。我们的发现是重要的是出于多种原因。首先，已显示脂肪细胞可以改善疤痕，但成熟的脂肪细胞如何在此过程中的功能尚不清楚。其次，脂肪组织损失是皮肤的主要临床问题，早期皮肤纤维化发展的事件。此外，脂肪细胞及其衍生物（脂肪酸和/或细胞因子）是一种可导致的细胞类型，可创建个性化疗法，以促进纤维化患者的愈合。通过两个集中和互补的特定目标，本申请中提出的工作将进行多种遗传小鼠模型的优势，这些模型允许脂肪细胞脂解和纤维化的特定废除发育，脂肪组学和成纤维细胞培养测定法，以定义皮肤期间脂肪细胞脂肪的功能纤维化。我们的目标是测试是否：1。脂肪细胞衍生的脂肪酸在纤维化过程中消除ECM的产生发展;和2。Wnts刺激皮肤脂肪细胞的脂解。朝着这些目标，在AIM1中，我们将定义细胞和分子的变化，脂解会改变小鼠皮肤以及皮肤脂肪细胞脂质可以废除小鼠和人类纤维化成纤维细胞或其他细胞类型中的纤维化反应。在AIM2中，我们将测试 WNT及其新的候选效应子的作用，二肽基二肽酶4在化学和体内和体外的遗传模型。这些研究的结果将为衍生的真皮脂肪细胞提供作用脂肪酸和Wnt信号靶标作为慢性皮肤纤维化和相关的新治疗靶标的脂肪营养不良。影响：我们建议研究脂肪细胞脂质的功能和Wnt信号传导在真皮纤维化。这些结果将揭示脂质耗竭涉及的新细胞类型和分子途径这可能是纤维化发育和逆转的关键调节剂。这些实验的结果将阐明作为新参与者的皮内脂肪细胞和脂肪分解的贡献，将通过开放来改变现场新的查询和治疗靶标线。