Role of IFN kappa in psoriasis-mediated diabetes development

项目摘要/摘要 最近的文献表明，牛皮癣，一种流行的慢性炎症性皮肤病，与 2型糖尿病(T2D)的风险增加。这一点很重要，因为牛皮癣和T2D的组合恶化 在更大程度上控制血糖，导致继发性并发症比任何一种疾病单独发生的都要多； 然而，导致银屑病患者发生T2D的分子机制尚不清楚。在……里面 银屑病，干扰素κ(干扰素kappa)，一种I型干扰素，在皮损和外周血中增加，导致 全身炎症。我们的初步数据确定了一种组蛋白甲基转移酶，混合血统白血病 蛋白1(MLL1)可以控制角质形成细胞干扰素κ的表达，这可能是由 TYK2/STAT1信号转导。角质形成细胞过度表达IFNK与炎症增加有关 巨噬细胞(MΦS)在皮肤和脂肪组织中与高血糖的发生发展。为此，我们初步的 资料表明，角质形成细胞来源的干扰素κ可通过JMJD3-1驱动MΦS向炎症表型转变。 中介机制。此外，我们的研究小组还发现JMJD3，一种组蛋白去甲基酶，在 调节皮肤炎症MΦS，MΦS在干扰素κ/JAK1/STAT3刺激后上调。这 K99/R00提案试图验证TYK2/STAT1信号上调角质形成细胞MLL1的假设 干扰素κ在银屑病中的过度表达是其机制之一。此外，我们建议干扰素κ的这种增加 由银屑病角质形成细胞驱动MΦS皮肤和脂肪组织的炎症表型通过a JMJD3介导的机制。这些炎性脂肪组织巨噬细胞(ATM)然后驱动脂肪细胞 通过调节PPARγ和GLUT4来调节代谢功能障碍。为了检验这些假设，我们将继续 本奖项K99阶段的以下目标：目标1：确定MLL1介导的机制(S)，通过 角质形成细胞干扰素κ在银屑病组织中的表达调节目的2：研究角质形成细胞干扰素的作用机制(S) 角质形成细胞来源的干扰素κ调节银屑病患者的M-Φ表型。在此期间，PI将接受研究 表观遗传技术培训、分离和培养人角质形成细胞、序列分析和分离 脂肪组织中的巨噬细胞。在独立阶段(R00)，她将确定机制(S) 通过ATM来源的肿瘤坏死因子α对银屑病患者脂肪细胞糖代谢的调节，并确定干扰素κ 抑制可改善葡萄糖代谢(目标3)。在K99阶段进行的拟议技术培训将 为私人投资经理提供必要的技能，使其能够成功地开展独立研究项目，研究这种关系 慢性皮肤炎症性疾病和代谢功能障碍之间的关系。

PROJECT SUMMARY/ABSTRACT Recent literature has identified that psoriasis, a prevalent chronic inflammatory skin disease, is associated with an increased risk of type 2 diabetes (T2D). This is important since the combination of psoriasis and T2D worsen glycemic control to a greater degree, leading to increased secondary complications than either disease alone; however, the molecular mechanisms that predispose patients with psoriasis to develop T2D are unknown. In psoriasis, interferon kappa (IFNκ), a type I IFN, is increased in skin lesions and peripheral blood, leading to systemic inflammation. Our preliminary data identifies that a histone methyltransferase, Mixed lineage leukemia protein 1 (MLL1), may control IFNκ expression in keratinocytes, and this may be mechanistically driven by Tyk2/STAT1 signaling. This overexpression of IFNk by keratinocytes is associated with increased inflammatory macrophages (MΦs) in skin and adipose tissue and hyperglycemia development. To this end, our preliminary data identify that keratinocyte-derived IFNκ can drive MΦs towards an inflammatory phenotype via a JMJD3- mediated mechanism. Further, our group has identified that JMJD3, a histone demethylase, is crucial in regulating inflammatory MΦs in skin and is upregulated in MΦs following IFNκ/JAK1/STAT3 stimulation. This K99/R00 proposal seeks to test the hypothesis that Tyk2/STAT1 signaling upregulates MLL1 in keratinocytes and mechanistically underlies IFNκ overexpression in psoriasis. Further, we propose that this increase in IFNκ by psoriatic keratinocytes drives MΦs towards an inflammatory phenotype in skin and adipose tissue via a JMJD3-mediated mechanism. These inflammatory adipose tissue macrophages (ATMs) then drive adipocyte metabolic dysfunction via regulation of PPARγ and GLUT4. To test these hypotheses, We will pursue the following aims during the K99 phase of this award: AIM 1: Identify the MLL1-mediated mechanism(s) by which keratinocyte IFNκ expression is regulated in psoriasis tissue, AIM 2: Examine the mechanism(s) by which keratinocyte-derived IFNκ regulates MΦ phenotype in psoriasis. During this time, the PI will receive research training in epigenetic techniques, isolating and culturing human keratinocytes, sequence analysis, and isolating macrophages from adipose tissue. During the independent phase(R00), she will determine the mechanism(s) by which ATM-derived TNFα dysregulates adipocyte glucose metabolism in psoriasis and determine if IFNκ inhibition improves glucose metabolism (AIM 3). Training in the proposed techniques during the K99 phase will afford the PI the necessary skills to run a successful independent research program studying the relationship between chronic skin inflammation diseases and metabolic dysfunction.