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

描述（由申请人提供）：正常毛囊皮脂腺单位（PSU）和瘢痕性脱发中的PPAR-gamma信号传导摘要原发性瘢痕性或瘢痕性脱发（CA）的特征在于毛囊中心性炎症，最终毛囊被纤维组织替代，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。我们的研究与淋巴细胞CA，苔藓planopilaris（LPP），取得了新的结果，提供了线索的疾病的发病机制。我们最近发现，在淋巴细胞性CA扁平苔藓（LPP）中，PPAR信号丢失，毛囊干细胞中的靶向PPAR缺失导致瘢痕性脱发。然而，在LPP中负责损失的PPAR信号转导的机制尚不清楚。我们的新数据表明，芳烃受体（AhR），最有名的介导二恶英的毒性，是显着上调LPP和在PPARKO小鼠。体外培养的毛囊外根鞘（ORS）细胞中，PPAR与AhR之间存在相互拮抗的调节作用。我们表明，干细胞标志物（LGR 5，LHX 2，SOX 9，TCF 3）的表达减少，细胞因子，生长因子和组织重塑基因在LPP和PPAR KO小鼠中上调。我们推测，PPAR与AhR的功能相互作用在毛囊皮脂腺单位（PSU）的稳态、毛囊的生长和毛囊的发育中起着重要作用。 干细胞动力学和CA疾病进展。该提案的总体目标是阐明AhR调节PPAR的机制，并描述这种串扰对毛囊外根鞘（ORS）细胞在体外和瘢痕性脱发疾病进展过程中的机制作用。我们将使用人体组织（正常、未受影响和受影响的原发性CA活检组织）、ORS细胞、我们开发的PPAR干细胞特异性KO小鼠模型和K14-AhR 转基因小鼠在目标1中，我们将检验AhR之间存在相互功能抑制的假设。 和过氧化物酶体增殖物激活体受体，异常的过氧化物酶体增殖物激活体受体信号参与所有CA的发病机制。目的2的重点是研究PPAR-AhR串扰对体外毛囊ORS细胞的作用机制及其对CA瘢痕形成和纤维化的影响。在目标3中，我们将确定干细胞特异性PPAR消融或AhR组成性激活对PSU和瘢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。过氧化物酶体增殖物激活物受体激动剂对调节 将在动物模型中测试朝向正常状态的免疫激活和恢复正常毛发功能和再生长。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嗜中性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学需求。PHS 398/2590（Rev. 11/07） 公共卫生相关性：这项建议将确定核受体，过氧化物酶体增殖物激活受体的活性丧失是否是疤痕性脱发永久性脱发的原因。它还将确定异生素反应受体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靶向效应物为毛发和皮肤疾病的靶向治疗提供了基础。PHS 398/2590（Rev. 11/07）

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