Defining the role of lymphatic vessels in wound healing

定义淋巴管在伤口愈合中的作用

基本信息

批准号：
10596468
负责人：
Valerie Horsley
金额：
$ 50.33万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596468
关键词：
Affect Aging American Angiogenesis Inhibition Apoptosis Area Biology Blood Blood Vessels Cell Culture Techniques Cell physiology Cell surface Cells Chronic Cicatrix Collaborations Data Defect Dermal Diabetes Mellitus Diabetic mouse Endocytosis Inhibition Endothelial Cells Endothelium Epithelial Cells Extracellular Matrix Fibroblasts Fibrosis Generations Genetic Genomics Goals Heterogeneity Homeostasis Human Hypervascular In Vitro Injury KDR gene Laboratories Lymphangiogenesis Lymphatic Lymphatic Diseases Lymphatic Endothelial Cells Lymphatic Endothelium Lymphatic function Lymphedema Malignant Neoplasms Measures Modeling Molecular Mus Natural regeneration Operative Surgical Procedures Pathologic Patients Phase Population Process Production Proliferating Regulation Risk Role Signal Pathway Skin Skin Aging Skin repair Skin wound healing Swelling System Testing Tissue Expansion Tissues VEGFC gene Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factor Receptor-3 Work aged angiogenesis chronic wound defined contribution diabetic diabetic patient endothelial regeneration experimental study healing human disease improved in vitro Assay in vivo lymphatic malformations lymphatic vessel mRNA Expression mathematical model mouse model new therapeutic target non-healing wounds novel older patient overpopulation regenerative regenerative therapy regenerative tissue repaired single-cell RNA sequencing skin disorder skin fibrosis skin regeneration skin wound therapeutic target wound wound healing

项目摘要

My laboratory recently uncovered an unexpected and intriguing role for a lymphatic vessels during skin wound healing. In particular, we identified that mice without lymphatic vessels display hypervascular regeneration and fibrosis after injury. Our findings are important for several reasons. First, while lymphatic vessels have been shown to be important for skin repair, the precise function of these cells in skin repair is poorly understood. Second, our data reveal that unknown mechanisms involving lymphatic vessels control blood vessel repair and skin fibrosis, two conditions that impact wound healing and excessive scarring. Finally, lymphedema, a chronic, debilitating and incurable swelling that can be a result of damage to the lymphatic vessel system due to surgery, cancer, treatments, or injury, affects over 10 million Americans. Through these focused and complementary Specific Aims, the work proposed in this application will take advantage of multiple genetic mouse models that allow specific depletion of lymphatic vessels, state of the art genomics, cell culture models. We will (1) identify the cellular and molecular mechanisms that drive lymphatic endothelial regeneration in the skin, (2) analyze the function of lymphatic endothelium cells in suppressing blood vessel repair and contributing to fibrosis, and (3) define whether enhancing lymphatic vessel repair ameliorates defective wounds of aged and diabetic mice. These studies will identify specific pro-healing cells and molecular mechanisms that can be utilized to promote healing in human patients with defective wound healing or lymphatic disorders.

我的实验室最近发现淋巴管在皮肤伤口过程中发挥着意想不到且有趣的作用康复。特别是，我们发现没有淋巴管的小鼠表现出丰富的血管再生和损伤后纤维化。我们的发现很重要，原因有几个。首先，虽然淋巴管已经研究表明这些细胞对皮肤修复很重要，但人们对这些细胞在皮肤修复中的确切功能知之甚少。其次，我们的数据揭示了涉及淋巴管的未知机制控制血管修复和皮肤纤维化，这是影响伤口愈合和过度疤痕的两种情况。最后，淋巴水肿，一种慢性由于淋巴管系统受损而导致的使人衰弱且无法治愈的肿胀手术、癌症、治疗或受伤影响着超过 1000 万美国人。通过这些集中和互补的具体目标，本申请中提出的工作将利用多种遗传允许特定淋巴管耗竭的小鼠模型、最先进的基因组学、细胞培养模型。我们将 (1) 确定驱动淋巴管内皮再生的细胞和分子机制皮肤，（2）分析淋巴管内皮细胞抑制血管修复的功能促进纤维化，以及（3）确定增强淋巴管修复是否可以改善有缺陷的伤口老年小鼠和糖尿病小鼠。这些研究将确定特定的促愈合细胞和分子机制可用于促进伤口愈合不良或淋巴疾病的人类患者的愈合。