Adipocyte lipolysis regulates skin repair

脂肪细胞脂肪分解调节皮肤修复

基本信息

批准号：
10407696
负责人：
Valerie Horsley
金额：
$ 0.53万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407696
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

项目摘要

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.

项目概要我的实验室最近发现成熟脂肪细胞在皮肤伤口过程中发挥着意想不到的有趣作用愈合：控制受伤后的炎症。特别是，我们发现成熟的脂肪细胞会发生脂肪分解将脂质释放到伤口床中引发炎症。我们的发现很重要，原因有几个。第一的，脂肪细胞已被证明可以改善伤口愈合和疤痕形成，但成熟的脂肪细胞如何在这方面发挥作用过程不清楚。其次，脂肪细胞中脂质的释放或脂肪分解已被证明可以调节传统仓库中的炎症，但皮肤脂肪细胞是否调节基本的炎症过程皮肤损伤后的情况尚不清楚。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并抑制伤口愈合，但是否糖皮质激素对伤口愈合的影响是通过脂肪细胞介导的尚不清楚。通过三重点突出和互补的具体目标，本申请中提出的工作将利用多个允许特定脂肪细胞消耗、脂肪细胞脂肪分解、脂质组学、脂质追踪的遗传小鼠模型，生物工程组织模型，以及定义脂肪细胞衍生功能的新型生物分析平台皮肤损伤期间的脂质以及这些脂质如何随着糖皮质激素、年龄、糖尿病和肥胖而改变。我们将 (1) 确定脂肪细胞衍生的脂质在皮肤伤口愈合过程中炎症过程中的作用，（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来影响伤口愈合，(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发生改变皮肤。这些研究将确定特定的促愈合细胞群和分子，可用于促进伤口愈合不良或其他皮肤疾病的人类患者的愈合。