PPAR-gamma Signaling in Normal Pilosebaceous Units and in Scarring Alopecia

正常毛囊皮脂腺单位和疤痕性脱发中的 PPAR-gamma 信号转导

基本信息

批准号：
8123197
负责人：
Pratima Karnik
金额：
$ 33.57万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-28 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8123197
关键词：
AHR gene Ablation Address Affect Agonist Alopecia Alopecia Areata Animal Model Aryl Hydrocarbon Receptor Biological Assay Biological Markers Biological Process Biopsy COL1A1 gene CYP1A1 gene Cell Cycle Kinetics Cell Proliferation Cell physiology Cells Chronic Cicatrix Classification Clinical Complex Cutaneous Data Dermis Development Dioxins Disease Disease Progression Epidermal Growth Factor Receptor Epidermis Epithelial Epithelial Cells Event Extracellular Matrix Fibroblasts Fibrosis Folliculitis Functional disorder Gene Targeting Genes Goals Growth Growth Factor Hair Hair follicle structure Healed Health Histologic Homeostasis Immunofluorescence Immunologic Immunohistochemistry In Vitro Inflammation Inflammatory Injury Integrins Knockout Mice LHX2 gene Lead Lichen planopilaris Link Literature Lymphocyte Mediating Medical Mesenchymal Messenger RNA Molecular Monitor Mus Myofibroblast Natural regeneration Normal Cell Normalcy Nuclear Receptors Organ PPAR gamma Pathogenesis Pathology Peptide Hydrolases Peroxisome Proliferator-Activated Receptors Phenocopy Phenotype Physiological Processes Plant Roots Play Preventive Principal Investigator Process Proteins Receptor Activation Receptor Cross-Talk Receptor Signaling Regulation Reporter Genes Repression Response Elements Role Sampling Scalp structure Sebaceous Glands Seborrheic dermatitis Signal Pathway Signal Transduction Signal Transduction Pathway Staining method Stains Stem cells TCF3 gene TNF gene Testing Therapeutic Therapeutic Intervention Time Tissues Toxic effect Transgenic Mice Western Blotting Wound Healing Xenobiotics aryl hydrocarbon receptor ligand base cdc Genes cell motility chromatin immunoprecipitation cytokine fibrogenesis healing human tissue immune activation improved in vitro Assay in vivo inhibitor/antagonist insight lipid metabolism mRNA Expression migration mouse model neutrophil novel novel diagnostics novel therapeutics osteopontin prevent programs promoter protein expression receptor receptor expression repaired research study response

项目摘要

DESCRIPTION (provided by applicant): PPAR-gamma Signaling in Normal Pilosebaceous Units (PSU) and in Scarring Alopecia ABSTRACT Primary cicatricial or scarring alopecia (CA) are characterized by a folliculocentric inflammation with the ultimate replacement of the follicle with fibrous tissue and progressive and permanent hair loss. However, the cause of the inflammatory attack and the molecular pathogenesis has yet to be elucidated. Our studies with the lymphocytic CA, Lichen planopilaris (LPP), have yielded novel results which provide clues to disease pathogenesis. We have recently shown that PPAR signaling is lost in lichen planopilaris (LPP), a lymphocytic CA, and that targeted deletion of PPAR in stem cells of the hair follicle causes scarring alopecia. However, the mechanisms responsible for loss of PPAR signaling in LPP are not understood. Our new data shows that the Aryl Hydrocarbon Receptor (AhR), best known for mediating the toxicity of dioxin, is significantly upregulated in LPP and in the PPAR KO mouse. Furthermore, a mutually antagonistic regulation exists between PPAR and AhR in hair follicle outer root sheath (ORS) cells in vitro. We show that the expression of stem cell markers (LGR5, LHX2, SOX9, TCF3) is decreased and that cytokines, growth factors and tissue remodeling genes are upregulated in LPP and in the PPAR KO mouse. We hypothesize that functional interplay of PPAR with AhR has a central role in pilosebaceous unit (PSU) homeostasis, hair follicle stem cell kinetics and disease progression in CA. The overall goals of this proposal are to elucidate the mechanisms by which AhR modulates PPAR and to delineate the mechanistic effects of this cross-talk on hair follicle outer root sheath (ORS) cells in vitro and during disease progression in scarring alopecia. We will test this hypothesis using a combination of human tissue (normal, unaffected and affected primary CA biopsies), ORS cells, the PPAR stem cell specific KO mouse model that we have developed and the K14-AhR transgenic mouse. In Aim 1, we will test the hypothesis that a mutual functional repression exists between AhR and PPAR and that aberrant PPAR signaling is involved in the pathogenesis of all CA. The focus of Aim 2 is to investigate the mechanistic effects of PPAR- AhR cross-talk on hair follicle ORS cells in vitro and its implications for scarring and fibrosis in CA. In Aim 3, we will determine the effects of stem cell specific PPAR ablation or AhR constitutive activation on the PSU and in the development of scarring alopecia. The effect of these changes on hair follicle stem cell kinetics will be investigated. The efficacy of PPAR agonists to modify immune activation toward normalcy and restore normal hair function and re-growth in the animal model will be tested. These studies provide a novel framework for understanding the role of PPAR in the pathophysiology of primary CA, they provide novel diagnostic biomarkers, facilitate the classification of clinically distinct lymphocytic and neutrophilic CA and suggest potential new therapeutic strategies, thereby addressing an important medical need. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: This proposal will determine if the loss of activity of the nuclear receptor, PPAR, is the cause of permanent hair loss in scarring alopecia. It will also determine whether the xenobiotic response receptor, AhR, has a role in inhibiting PPAR. PPAR has broad-range effects in controlling inflammation and regulating lipid metabolism. Because this nuclear receptor is important for normal hair follicle health, understanding its regulatory mechanisms and target effectors provides a basis for targeted therapy in hair and cutaneous diseases. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

描述（由申请人提供）：正常毛s骨单元（PSU）和疤痕型脱发的PPAR-GAMMA信号传导，抽象的原发性果胶或疤痕型脱发（CA）的特征是卵泡中心炎症，并具有纤维组织和纤维组织以及纤维组织和纤维组织的最终替代永久脱发。但是，炎症攻击和分子发病机理的原因尚未阐明。我们对淋巴细胞CA，地衣planopilaris（LPP）的研究产生了新的结果，为疾病发病机理提供了线索。我们最近表明，PPAR信号传导在地衣planopilaris（LPP）（淋巴细胞CA）中丢失，并且靶向毛囊干细胞中PPAR的靶向缺失会导致疤痕性脱发。但是，尚不清楚导致LPP中PPAR信号丢失的机制。我们的新数据表明，在LPP和PPAR KO小鼠中，芳基烃受体（AHR）在介导二恶英的毒性中最著名。此外，在体外，毛囊外鞘（ORS）细胞中PPAR和AHR之间存在相互拮抗的调节。我们表明，干细胞标记（LGR5，LHX2，SOX9，TCF3）的表达减少，并且在LPP和PPAR KO小鼠中，细胞因子，生长因子和组织重塑基因上调。我们假设PPAR与AHR的功能相互作用在CA中的毛s骨单位（PSU）稳态，毛囊干细胞动力学和疾病进展中具有核心作用。该提案的总体目标是阐明AHR调节PPAR的机制，并描绘出该串扰对毛囊外部鞘（ORS）细胞（ORS）细胞（ORS）细胞（ORS）细胞的机械作用，以及在脱发性疤痕中疾病进展过程中的疾病进展。我们将使用人体组织（正常，未受影响和影响的原发性CA活检），ORS细胞，我们开发的PPAR干细胞特异性KO小鼠模型以及K14-AHR转基因小鼠的PPAR干细胞特异性KO小鼠模型来检验这一假设。在AIM 1中，我们将检验以下假设：AHR和PPAR之间存在相互功能抑制，并且异常的PPAR信号与所有CA的发病机理有关。 AIM 2的重点是研究PPAR-AHR串扰对毛囊ORS细胞体外及其对CA的疤痕和纤维化的影响的机械作用。在AIM 3中，我们将确定干细胞特异性PPAR消融或AHR构型激活对PSU和疤痕性脱发的发展的影响。这些变化对毛囊干细胞动力学的影响将研究。 PPAR激动剂将免疫激活朝着正常和恢复正常的头发功能和在动物模型中恢复的疗效将进行测试。这些研究为理解PPAR在原发性CA的病理生理学中的作用提供了一个新的框架，它们提供了新型的诊断生物标志物，促进了临床上不同淋巴细胞和嗜中性粒细胞性CA的分类，并提出了潜在的新治疗策略，从而解决了一种重要的医疗需求。 PHS 398/2590（Rev. 11/07）页面延续格式页面公共卫生相关性：该提案将确定核受体PPAR活动丧失是否是疤痕脱发的永久脱发的原因。它还将确定异种生物反应受体AHR是否在抑制PPAR中起作用。 PPAR在控制炎症和调节脂质代谢方面具有广泛的影响。由于该核受体对于正常的毛囊健康很重要，因此了解其调节机制和目标效应器为靶向治疗头发和皮肤病提供了基础。 PHS 398/2590（Rev. 11/07）页面延续格式页面