Trim32 Regulation of Piasy in Skin Homeostasis

Trim32 对 Piasy 皮肤稳态的调节

• 批准号: 8259191
• 负责人: MOLLY F. KULESZ-MARTIN
• 金额: $ 32.93万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259191
• 关键词: 19p13; Acanthosis; Apoptosis; Apoptotic; Atopic Dermatitis; CCL20 gene; CCR6 gene; Cell Survival; Cells; Chromosomes; Death Rate; Dendritic Cells; Dermal; Development; Disease; Environment; Enzymes; Epidermis; Equilibrium; Feedback; Fostering; Genes; Growth; Homeostasis; Human; Hyperplasia; IL17 gene; ITGAX gene; Immune; Immune system; In Vitro; Infiltration; Inflammation; Inflammatory; Interleukin-17; Knockout Mice; Lead; Lesion; Ligase; Link; Lymphocyte; Mediating; Modeling; Molecular; Mus; NF-kappa B; Organ; Parakeratosis; Partner in relationship; Pathogenesis; Pathway interactions; Patients; Phenotype; Predisposition; Production; Proteins; Psoriasiform Dermatitis; Psoriasis; Regulation; Role; Severities; Skin; Symptoms; TNF gene; Testing; Th2 Cells; Therapeutic; Tissue Sample; Transgenic Mice; Up-Regulation; base; chemokine; cytokine; human disease; in vivo; inhibitor/antagonist; interleukin-22; interleukin-23; keratinocyte; mouse model; response; skin disorder; transcription factor; treatment strategy; ubiquitin-protein ligase

PROJECT SUMMARY There is a vicious circle in psoriasis that disrupts epidermal homeostasis through alterations in keratinocytes (hyperproliferation, parakeratosis) and immunocytes (infiltration and activation). While it is well known that uncontrolled keratinocyte proliferation is largely driven by pro-inflammatory cytokines from the immunocytes, the functional role of keratinocytes in the recruitment and activation of immunocytes is poorly understood. We have discovered intriguing links between Trim32 (an E3 ubiquitin ligase), its substrate Piasy (an E3 SUMO ligase), and psoriasis. Trim32 is elevated in psoriasis tissue samples compared to non-lesional control epidermis. Trim32 negatively regulates the pro-apoptotic Piasy protein, a repressor of NF-kB, STAT, and SMAD transcription factors that have been implicated in the pathogenesis of psoriasis. The Piasy gene resides in the PSORS6 susceptibility locus on chromosome 19p13, although the significance of this remains to be determined. We have found that Trim32 activates and Piasy inhibits keratinocyte production of CCL20, a chemokine increased in psoriatic lesions that is a major factor in recruitment of dendritic cells and Th17 lymphocytes to the skin. The CCL20 induction by TNFa and IL17 cytokines is mediated through the activation of NF-kB. These findings lead us to hypothesize that Trim32 and Piasy are part of a positive feedback loop of CCL20 overproduction by keratinocytes and Th17 activation that contributes to the cycle of psoriasis. Initial evidence suggests that Trim32 is not simply a general marker of epidermal hyperplasia because its elevation in psoriasis, recognized as a Th17 disease, is not shared by atopic dermatitis, recognized as a Th2 cell disease, and because upregulation of CCL20 in keratinocytes responds to Th17 but not Th1 or Th2 cytokines. We propose to define the role of Trim32 and Piasy in psoriasis according to the following aims: 1) determine molecular pathways of Trim32 and Piasy regulation of CCL20 production in keratinocytes in response to Th17 cytokines, in particular through the NF-kB pathway, and evaluate the effects of Trim32 and Piasy on the dermal recruitment of CD11c+ dendritic cells and Th17 cells; 2) explore the functional role of Trim32 and Piasy in keratinocyte survival and epidermal acanthosis in response to Th17 activation, using in vitro and in vivo approaches, and determine the impact of Trim32 KO and Piasy KO on the severity of phenotypes in two mouse models of psoriasiform dermatitis; and 3) evaluate the role of Trim32 and Piasy in CCL20 expression, inflammation and keratinocyte apoptosis in psoriasis and atopic dermatitis. Ultimately, these studies may impact our understanding of the molecular mechanisms of psoriasis as distinct from atopic dermatitis and lead to rational improvement of treatment strategies for psoriasis patients.

项目摘要 牛皮癣中有一个恶性循环，通过角质形成细胞的改变来破坏表皮稳态 （高增生，巴拉菌病）和免疫细胞（浸润和激活）。虽然众所周知 不受控制的角质形成细胞增殖主要是由免疫细胞的促炎细胞因子驱动的， 角膜细胞在免疫细胞的募集和激活中的功能作用知之甚少。我们 已经发现了Trim32（E3泛素连接酶）之间的有趣联系，其底物Piasy（E3 Sumo 连接酶）和牛皮癣。牛皮癣组织样品中的TRIM32升高 表皮。 TRIM32负调节促凋亡的piasy蛋白，NF-KB，Stat和STAT的阻遏物 SMAD转录因子与牛皮癣的发病机理有关。朴素基因属于 在19p13染色体上的psors6易感性基因座中，尽管其重要性尚有 决定。我们发现TRIM32激活和轻质抑制CCL20的角质形成细胞的产生，A 银屑病病变中的趋化因子增加，这是树突状细胞募集和Th17的主要因素 皮肤的淋巴细胞。 TNFA和IL17细胞因子的CCL20诱导是通过激活介导的 nf-kb。这些发现使我们假设Trim32和Piasy是一个正面反馈回路的一部分 CCL20由角质形成细胞和Th17激活过量产生，导致牛皮癣的周期。最初的 有证据表明，TRIM32不仅是表皮增生的一般标记，因为它的升高 牛皮癣是一种被认为是Th17疾病的牛皮癣。 并且由于角质形成细胞中CCL20的上调对TH17的反应，但无反应Th1或Th2细胞因子。我们 根据以下目的，建议定义Trim32和Piasy在牛皮癣中的作用：1）确定 TRIM32的分子途径和CCL20生产的角质形成细胞中的PIASY调节，响应于Th17 细胞因子，尤其是通过NF-KB途径，并评估Trim32和Piasy对 CD11C+树突状细胞和Th17细胞的真皮募集； 2）探索TRIM32和PIASY的功能作用 在角质形成细胞的生存和表皮棘皮动物中，响应于Th17激活，使用体外和体内 方法，并确定Trim32 KO和Piasy KO对两个表型严重程度的影响 牛皮癣状皮炎的小鼠模型； 3）评估Trim32和Piasy在CCL20表达中的作用， 牛皮癣和特应性皮炎的炎症和角质形成细胞凋亡。最终，这些研究可能 影响我们对牛皮癣分子机制的理解，与特应性皮炎不同，并铅 合理改善牛皮癣患者的治疗策略。