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

描述（由申请人提供）：正常毛囊皮脂腺单位（PSU）和疤痕性脱发中的 PPAR-γ 信号传导 摘要 原发性疤痕性或疤痕性脱发（CA）的特征是毛囊中心炎症，最终以纤维组织取代毛囊以及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未阐明。我们对淋巴细胞 CA、扁平苔藓 (LPP) 的研究取得了新的结​​果，为疾病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 CA）中丢失，并且毛囊干细胞中 PPAR 的靶向缺失会导致疤痕性脱发。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基烃受体 (AhR) 在 LPP 和 PPAR KO 小鼠中显着上调。此外，体外毛囊外根鞘（ORS）细胞中PPAR和AhR之间存在相互拮抗的调节。我们发现，LPP 和 PPAR KO 小鼠中干细胞标记物（LGR5、LHX2、SOX9、TCF3）的表达降低，细胞因子、生长因子和组织重塑基因上调。我们假设 PPAR 与 AhR 的功能相互作用在毛囊皮脂腺单位 (PSU) 稳态、毛囊干细胞动力学和 CA 疾病进展中发挥核心作用。该提案的总体目标是阐明 AhR 调节 PPAR 的机制，并描述这种串扰在体外和疤痕性脱发疾病进展过程中对毛囊外根鞘 (ORS) 细胞的机制影响。我们将使用人体组织（正常、未受影响和受影响的原发性 CA 活检）、ORS 细胞、我们开发的 PPAR 干细胞特异性 KO 小鼠模型和 K14-AhR 转基因小鼠的组合来测试这一假设。在目标 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 信号传导参与所有 CA 的发病机制。目标 2 的重点是研究 PPAR-AhR 串扰对体外毛囊 ORS 细胞的机制影响及其对 CA 疤痕和纤维化的影响。在目标 3 中，我们将确定干细胞特异性 PPAR 消融或 AhR 组成型激活对 PSU 以及疤痕性脱发发展的影响。将研究这些变化对毛囊干细胞动力学的影响。将在动物模型中测试 PPAR 激动剂将免疫激活调整至正常状态并恢复正常毛发功能和重新生长的功效。这些研究为理解 PPAR 在原发性 CA 病理生理学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，促进了临床上不同的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。 PHS 398/2590（修订版 11/07） 页面延续 格式页面 公共健康相关性：该提案将确定核受体 PPAR 活性丧失是否是疤痕性脱发中永久性脱发的原因。它还将确定异生物质反应受体 AhR 是否具有抑制 PPAR 的作用。 PPAR 在控制炎症和调节脂质代谢方面具有广泛的作用。由于这种核受体对正常毛囊健康很重要，因此了解其调节机制和目标效应器为毛发和皮肤疾病的靶向治疗奠定了基础。 PHS 398/2590（修订版 11/07） 页面延续 格式页面