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 银屑病是一种恶性循环，通过角质形成细胞的改变破坏表皮的稳态 （过度增殖、角化不全）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由来自免疫细胞的促炎细胞因子驱动， 角质形成细胞在免疫细胞的募集和活化中的功能作用知之甚少。我们 我发现Trim 32（一种E3泛素连接酶），其底物Piasy（一种E3 SUMO） 连接酶）和牛皮癣。与非病变对照相比，银屑病组织样品中Trim 32升高 表皮Trim 32负调节促凋亡Piasy蛋白，一种NF-kB，STAT和 SMAD转录因子与银屑病发病机制有关。Piasy基因 在染色体19 p13上的PSORS 6易感基因座中，尽管这一点的意义仍有待进一步研究。 测定我们发现Trim 32激活角质形成细胞产生CCL 20，而Piasy抑制CCL 20， 银屑病皮损中趋化因子增加，是树突状细胞和Th 17募集的主要因素 淋巴细胞到皮肤。通过TNF α和IL 17细胞因子的CCL 20诱导是通过活化 NF-KB这些发现使我们假设Trim 32和Piasy是一个正反馈循环的一部分， 角质形成细胞过度产生CCL 20和Th 17激活导致银屑病周期。初始 有证据表明，Trim 32不仅仅是表皮增生的一般标志物， 银屑病被认为是一种Th 17疾病，但特应性皮炎，被认为是一种Th 2细胞疾病， 并且因为角质形成细胞中CCL 20的上调响应于Th 17而不是Th 1或Th 2细胞因子。我们 建议根据以下目的来定义Trim 32和Piasy在银屑病中的作用：1）确定 Trim 32和Piasy调节角质形成细胞响应Th 17产生CCL 20的分子途径 本发明的目的是通过检测细胞因子，特别是通过NF-kB途径，来评估Trim 32和Piasy对细胞因子的影响，并评估Trim 32和Piasy对细胞因子的影响。 CD 11 c+树突状细胞和Th 17细胞的真皮募集; 2）探索Trim 32和Piasy的功能作用 在角质形成细胞存活和表皮棘皮症中响应于Th 17活化，使用体外和体内 方法，并确定Trim 32 KO和Piasy KO对两种表型严重程度的影响。 银屑病样皮炎的小鼠模型;和3）评价Trim 32和Piasy在CCL 20表达中的作用， 银屑病和特应性皮炎中炎症和角质形成细胞凋亡。最终，这些研究可能 影响我们对银屑病分子机制的理解，与特应性皮炎和铅不同， 合理改进银屑病患者的治疗策略。