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

• 批准号: 8528334
• 负责人: Kevin D Cooper
• 金额: $ 31.89万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8528334
• 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

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

摘要原发性瘢痕性或瘢痕性脱发（CA）以毛囊中心性炎症为特征，最终以纤维组织替代毛囊，并伴有进行性和永久性脱发。然而，炎症发作的原因和分子发病机制尚不清楚。我们对淋巴细胞CA扁平苔藓（LPP）的研究已经取得了新的结果，为疾病的发病机制提供了线索。我们最近发现，PPAR信号在扁平苔藓（LPP）（一种淋巴细胞性CA）中丢失，并且毛囊干细胞中PPAR的靶向缺失会导致瘢痕性脱发。然而，LPP中PPAR信号丢失的机制尚不清楚。我们的新数据表明，以介导二恶英毒性而闻名的芳烃受体（Aryl Hydrocarbon Receptor, AhR）在LPP和PPAR KO小鼠中显著上调。此外，PPAR和AhR在毛囊外根鞘（ORS）细胞中存在相互拮抗的调控作用。我们发现，在LPP和PPAR KO小鼠中，干细胞标志物（LGR5、LHX2、SOX9、TCF3）的表达降低，细胞因子、生长因子和组织重塑基因表达上调。我们假设PPAR与AhR的功能相互作用在CA的毛囊皮脂腺单位（PSU）稳态、毛囊干细胞动力学和疾病进展中起核心作用。本提案的总体目标是阐明AhR调节PPAR的机制，并描述这种相互作用对毛囊外根鞘（ORS）细胞在体外和瘢痕性脱发疾病进展中的机制作用。我们将使用人体组织（正常、未受影响和受影响的原发CA活检）、ORS细胞、我们开发的PPAR干细胞特异性KO小鼠模型和K14-AhR转基因小鼠来验证这一假设。在Aim 1中，我们将验证AhR和PPAR之间存在相互功能抑制的假设，以及PPAR信号异常参与所有CA的发病机制。Aim 2的重点是研究PPAR- AhR串扰对体外毛囊ORS细胞的机制作用及其对CA瘢痕和纤维化的影响。我们将确定干细胞特异性PPAR消融或AhR组成激活对PSU和瘢痕性脱发发展的影响。这些变化对毛囊干细胞动力学的影响将被研究。我们将在动物模型中测试PPAR激动剂对正常免疫激活和恢复正常头发功能和再生的功效。这些研究为理解PPAR在原发性CA病理生理中的作用提供了一个新的框架，它们提供了新的诊断生物标志物，促进了临床不同淋巴细胞性和中性粒细胞性CA的分类，并提出了潜在的新治疗策略，从而解决了重要的医疗需求。小灵通398/2590 （Rev. 11/07）页延续格式页