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:10582578
- 负责人:
- 金额:$ 48.2万
- 依托单位:
- 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:
- 关键词:AccelerationAdipocytesAdipose tissueAggressive FibromatosisAtopic DermatitisBiological AssayBiologyBleomycinCell TherapyCell physiologyCellsCessation of lifeChemical ModelsChemicalsChronicCicatrixClinicalCollaborationsDataDepositionDermalDermisDevelopmentDipeptidasesDiseaseDisease ProgressionEuropeEventExtracellular Matrix ProteinsFatty AcidsFelis catusFibroblastsFibrosisGenerationsGeneticGenetic ModelsGenomicsGoalsHeartHistologicHumanHypertrophic CicatrixImmunologicsImmunomodulatorsIn VitroKeloidKineticsLaboratoriesLipaseLipidsLipodystrophyLipolysisLungModelingMolecularMusOrganParticipantPathologicPathway interactionsPatientsProcessProductionProfibrotic signalProteomicsRepressionRoleSclerodermaSclerosisSignal InductionSignal PathwaySignal TransductionSkinStimulusTestingTherapeutic InterventionTissuesWNT Signaling PathwayWorkadipocyte biologycell typecytokinedietaryefficacious treatmentexperimental studyhealinghuman diseaseimprovedin vivoin vivo Modelindium-bleomycininsightlipidomicsmouse modelnew therapeutic targetnovelpersonalized medicinepreventregenerative therapyresponseskin fibrosisskin organogenesistherapeutic targetuptake
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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RADHIKA P ATIT其他文献
RADHIKA P ATIT的其他文献
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{{ truncateString('RADHIKA P ATIT', 18)}}的其他基金
Substrate-mediated collective cell migration in calvarial bone expansion and disease
颅骨扩张和疾病中基质介导的集体细胞迁移
- 批准号:
10427074 - 财政年份:2021
- 资助金额:
$ 48.2万 - 项目类别:
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
- 批准号:
10361445 - 财政年份:2020
- 资助金额:
$ 48.2万 - 项目类别:
Mechanisms of apical expansion in calvarial bone morphogenesis
颅骨骨形态发生中根尖扩张的机制
- 批准号:
10056800 - 财政年份:2020
- 资助金额:
$ 48.2万 - 项目类别:
Mechanisms of apical expansion in calvarial bone morphogenesis
颅骨骨形态发生中根尖扩张的机制
- 批准号:
10212367 - 财政年份:2020
- 资助金额:
$ 48.2万 - 项目类别:
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
- 批准号:
9917422 - 财政年份:2020
- 资助金额:
$ 48.2万 - 项目类别:
Role of Wnt Signaling in Craniofacial Dermal Development
Wnt 信号转导在颅面真皮发育中的作用
- 批准号:
7667140 - 财政年份:2008
- 资助金额:
$ 48.2万 - 项目类别:
Genetic mechanisms of craniofacial dermal development
颅面真皮发育的遗传机制
- 批准号:
7901119 - 财政年份:2007
- 资助金额:
$ 48.2万 - 项目类别:
Genetic mechanisms of craniofacial dermal development
颅面真皮发育的遗传机制
- 批准号:
8113280 - 财政年份:2007
- 资助金额:
$ 48.2万 - 项目类别:
Genetic mechanisms of craniofacial dermal development
颅面真皮发育的遗传机制
- 批准号:
7299437 - 财政年份:2007
- 资助金额:
$ 48.2万 - 项目类别:
Genetic mechanisms of craniofacial dermal development
颅面真皮发育的遗传机制
- 批准号:
7470008 - 财政年份:2007
- 资助金额:
$ 48.2万 - 项目类别:
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