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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.

总结