Adipocyte lipolysis regulates skin repair

脂肪细胞脂肪分解调节皮肤修复

• 批准号: 10132731
• 负责人: Valerie Horsley
• 金额: $ 42.62万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132731
• 关键词: Acute; Adipocytes; Adipose tissue; Affect; Age; Aging; Bacterial Infections; Binding; Biological Assay; Cell physiology; Cells; Cicatrix; Collaborations; Data; Dermal; Dermis; Diabetes Mellitus; Diabetic mouse; Diagnostic; Fatty Acids; Fibrosis; Financial Hardship; Generations; Genetic; Glucocorticoid Receptor; Glucocorticoids; Goals; Growth; Hair; Healthcare Systems; Human; Infectious Skin Diseases; Inflammation; Inflammatory; Injury; Laboratories; Lead; Lipids; Lipolysis; Maintenance; Mediating; Metabolism; Mus; Nuclear Receptors; Obesity; Pathway interactions; Patients; Population; Process; Production; Role; Signal Transduction; Skin; Skin injury; Skin repair; Skin wound healing; Testing; Therapeutic; Tissue Engineering; Tissue Model; Tissues; Work; adipocyte biology; aged; base; cell type; chronic wound; cytokine; diabetic; diabetic patient; effective therapy; experimental study; healing; human disease; improved; injured; lipidomics; macrophage; monocyte; mouse model; novel; obese patients; personalized medicine; recruit; regenerative therapy; response; skin disorder; skin regeneration; skin wound; statistics; therapeutic target; therapy development; tissue repair; wound; wound bed; wound healing

Project Summary My laboratory recently uncovered an unexpected and intriguing role for mature adipocytes during skin wound healing: control of inflammation after injury. In particular, we identified that mature adipocytes undergo lipolysis to release of lipids into wound beds to initiate inflammation. Our findings are important for several reasons. First, adipocytes have been shown to improve wound healing and scarring yet how mature adipocytes function in this process is unclear. Second, the release of lipids from adipocytes, or lipolysis, has been shown to modulate inflammation in traditional depots, yet whether skin adipocytes regulate the essential inflammatory processes following skin injury is not known. 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 chronic wounds. Finally, glucocorticoids are known to influence adipocyte biology and also to inhibit wound healing, but whether the effect of glucocorticoids on wound healing is mediated through adipocytes is not known. Through three focused and complementary Specific Aims, the work proposed in this application will take advantage of multiple genetic mouse models that allow specific depletion of adipocytes, adipocyte lipolysis, lipidomics, lipid tracking, bioengineered tissue models, and a novel bioanalytical assay platform to define the function adipocyte-derived lipids during skin injury and how these are altered with glucocorticoids, age, diabetes and obesity. We will (1) identify the role of adipocyte derived lipids during inflammation during skin wound healing, (2) determine whether glucocorticoids influence wound healing through depletion of lipids from mature, dermal adipocytes, (3) define whether adipocyte fatty acids can modulate wound healing in aged and diabetic mice or are altered in human skin. These studies will identify specific pro-healing cell populations and molecules that can be utilized to promote healing in human patients with defective wound healing or other skin disorders.

项目摘要 我的实验室最近发现了一个意想不到的和有趣的作用，成熟脂肪细胞在皮肤创伤 愈合：控制损伤后的炎症。特别是，我们发现成熟脂肪细胞经历脂解作用， 释放脂质进入伤口床引发炎症。我们的发现很重要，原因有几个。第一、 脂肪细胞已被证明可以改善伤口愈合和瘢痕形成， 过程不清楚。第二，脂肪细胞释放脂质，或脂解，已被证明调节 然而，皮肤脂肪细胞是否调节基本的炎症过程， 皮肤损伤的原因尚不清楚。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，可用于创建个性化疗法，以促进慢性伤口患者的愈合。 最后，已知糖皮质激素会影响脂肪细胞生物学，也会抑制伤口愈合，但是否 糖皮质激素对伤口愈合的作用是通过脂肪细胞介导的，这是未知的。通过三 集中和互补的具体目标，本申请中提出的工作将利用多个 遗传小鼠模型允许脂肪细胞的特异性消耗、脂肪细胞脂解、脂质组学、脂质追踪 生物工程组织模型，和一种新的生物分析测定平台，以确定脂肪细胞来源的功能， 皮肤损伤期间的脂质以及糖皮质激素、年龄、糖尿病和肥胖如何改变这些脂质。我们会（1） 确定脂肪细胞衍生的脂质在皮肤伤口愈合期间的炎症过程中的作用，（2）确定是否 糖皮质激素通过消耗成熟真皮脂肪细胞中的脂质影响伤口愈合，（3）定义 脂肪细胞脂肪酸是否可以调节老年和糖尿病小鼠的伤口愈合或在人类中改变 皮肤这些研究将确定特定的促愈合细胞群和分子，可用于 促进具有缺陷伤口愈合或其它皮肤病的人类患者的愈合。