Adherens Junction dysfunction in Hidradenitis Suppurativa

项目摘要 化脓性汗腺炎（HS）是一种慢性、使人衰弱的炎症性皮肤病， 1-4%的人群皮肤褶皱中存在毛囊皮脂腺单位。它往往会导致毁容和永久疤痕。 组织学上，病变表现为表皮增生、毛囊异常和炎症。HS是 机械应力加剧1 -3。治疗通常包括手术和药物的结合 管理阿达木单抗是FDA唯一批准的治疗方法，对20-30%的患者有效。差距在我们 对HS所涉及的机制的理解排除了开发更有效和 针对这种使人衰弱、认识不足和经常误诊的疾病的靶向治疗。 我们发现，E-cad和p120连环蛋白（p120）的表达，这两个关键蛋白， 角质形成细胞粘附连接（AJ）的结构和功能，在23例严重HS病变的样本中有19例丢失。 即使在HS患者的非病变皮肤中，我们也观察到E-cad或p120完全丢失或易位， 细胞质此外，E-cad或p120蛋白丢失的程度与疾病的严重程度呈正相关。 AJ蛋白丢失在HS中的作用进一步被以下观察所证实： 它们的皮肤表现出HS样组织学特征。一个关键的问题是E-cad和p120的缺失是否有助于 疾病的过程是通过破坏角质形成细胞连接的稳定， 过程：我们认为这两者都是。 在这里，我们将严格调查角质细胞，不只是作为无辜的旁观者，但作为积极的 HS发病机制的贡献者。我们的数据表明，HS角质形成细胞粘附是在一个中心， 病理机制特征为前馈循环，其中粘附丧失驱动炎性细胞因子 表情这些细胞因子的表达进一步减弱粘附，这反过来又驱动细胞因子的进一步表达。 细胞因子，导致体内平衡的丧失和更多的炎症。因此，我们建议就此进行深入研究 致病循环，具有两个协同作用的目的，使用体外培养模型、鼠模型和来自 人类受试者，包括来自正常受试者和HS的角质形成细胞、血液和抽吸水疱液 患者在目标1中，我们将确定HS角质形成细胞中E-cad和p120的缺失如何促成HS 病理生理学在目标2中，我们将确定HS的炎症介质如何诱导E-cad，p120的丢失 和角质形成细胞中的粘附。我们将把我们的结果与受试者人口统计学和临床信息相关联 以确定与生物变量的任何关联。 本项目的成功完成将阐明角质形成细胞促进细胞增殖的机制。 HS中的炎症和组织破坏的致病循环。这些新知识对我们的整体 了解HS病理生理学。未来的治疗方法将来自于我们的努力， 新的HS病理机制，以支持NIAMS的目标，以改善这种衰弱性疾病的治疗。

Project Summary Hidradenitis Suppurativa (HS) is a chronic, debilitating inflammatory skin disease that affects the pilosebaceous units in skin folds in 1-4% of the population. It often leads to disfiguring and permanent scarring. Histologically, lesions exhibit epidermal hyperplasia, hair follicle abnormalities, and inflammation. HS is aggravated by mechanical stress1-3. Treatment often involves a combination of surgical and medical management. Adalimumab, the only FDA-approved therapy, is effective in 20-30% of patients. Gaps in our understanding of the mechanisms involved in HS preclude the development of more effective and targeted therapies for this debilitating, under-recognized and often misdiagnosed disease. We discovered that the expression of E-cadherin (E-cad) and p120 catenin (p120), two critical proteins for keratinocyte adherens junction (AJ) structure and function, is lost in 19 of 23 samples from severe HS lesions. Even in non-lesional skin from HS patients, we observe a complete loss or translocation of E-cad or p120 to the cytoplasm. Moreover, the degree of E-cad or p120 protein loss correlates positively with disease severity. A role for AJ protein loss in HS is further substantiated by the observation that mice lacking E-cad or p120 in their skin exhibit HS-like histological features. A key question is whether E-cad and p120 loss contributes to the disease process through destabilizing keratinocyte cell junctions or whether it results from the inflammatory process: we posit that it is both. Here, we will rigorously investigate keratinocytes, not just as innocent bystanders, but as active contributors to HS pathogenesis. Our data suggest that HS keratinocyte adhesion is at the center of a pathomechanism characterized by a feed forward cycle in which loss of adhesion drives inflammatory cytokine expression. Expression of these cytokines further weaken adhesion, which, in turn, drives further expression of cytokines, leading to loss of homeostasis and more inflammation. Therefore, we propose to delve into this pathogenic cycle with two synergistic aims using in vitro culture models, murine models, and samples from human subjects, including keratinocytes, blood, and suction blister fluid from both normal subjects and HS patients. In Aim 1, we will determine how the loss of E-cad and p120 in HS keratinocytes contributes to HS pathophysiology. In Aim 2, we will determine how inflammatory mediators of HS induce loss of E-cad, p120 and adhesion in keratinocytes. We will correlate our results with subject demographics and clinical information to determine any associations with biological variables. Successful completion of this project will elucidate the mechanism by which keratinocytes contribute to the pathogenic cycle of inflammation and tissue disruption in HS. This new knowledge is critical to our overall understanding of HS pathophysiology. Future therapeutic approaches will result from our efforts to discover new HS pathomechanisms in support of NIAMS goals to improve the treatment for this debilitating disease.