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

描述(申请人提供)：PPAR-γ信号在正常的毛发皮脂单位(PSU)和瘢痕性脱发中。摘要原发性瘢痕性或瘢痕性脱发(CA)的特征是毛囊中心性炎症，最终毛囊被纤维组织取代，并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。我们对淋巴细胞性CA扁平苔藓(LPP)的研究取得了新的结果，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)中丢失，这是一种淋巴细胞性CA，而毛囊干细胞中PPAR的靶向缺失会导致瘢痕性脱发。然而，导致LPP中PPAR信令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香烃受体(AhR)在LPP和PPAR KO小鼠中显著上调。此外，在体外培养的毛囊外根鞘细胞中，PPAR和AhR之间存在相互拮抗的调节。我们发现，在LPP和PPAR KO小鼠中，干细胞标记物(LGR5、LHX2、SOX9、TCF3)的表达减少，细胞因子、生长因子和组织重塑基因上调。我们假设PPAR和AhR的功能相互作用在毛囊皮脂单位(PSU)的动态平衡、毛囊干细胞动力学和CA的疾病进展中起核心作用。这项建议的总体目标是阐明AhR调节PPAR的机制，并描述这种串扰在体外和瘢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。我们将使用人类组织(正常、未受影响和受影响的原发CA活检)、ORS细胞、我们建立的PPAR干细胞特异性KO小鼠模型和K14-AhR转基因小鼠的组合来验证这一假设。在目标1中，我们将检验一种假设，即AhR和PPAR之间存在相互的功能抑制，并且PPAR信号异常参与了ALL CA的发病。目的2的重点是探讨PPAR-AhR串话对体外培养的毛囊ORS细胞的作用机制及其在CA瘢痕形成和纤维化中的意义。在目标3中，我们将确定干细胞特异性PPAR消融或AhR结构性激活对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。PPAR激动剂在动物模型中将免疫激活修改为正常状态并恢复正常毛发功能和重新生长的有效性将得到测试。这些研究为理解PPAR在原发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和中性粒细胞CA的分类，并提出了潜在的新的治疗策略，从而解决了一个重要的医学需求。PHS 398/2590(11/07版)页面续格式页面 公共卫生相关性：这项提案将确定核受体PPAR活性丧失是否是疤痕性脱发永久性脱发的原因。它还将确定异种反应受体AhR是否在抑制PPAR方面发挥作用。PPAR具有广泛的抗炎、调脂作用。由于这种核受体对正常毛囊的健康很重要，了解其调节机制和靶向效应因子为毛发和皮肤病的靶向治疗提供了基础。PHS 398/2590(11/07版)页面续格式页面

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