Role of IFN kappa in psoriasis-mediated diabetes development

IFN kappa 在银屑病介导的糖尿病发展中的作用

• 批准号: 10680608
• 负责人: Sonya J Wolf-Fortune
• 金额: $ 9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10680608
• 关键词: Adipocytes; Adipose tissue; Anti-Inflammatory Agents; Automobile Driving; Award; Cardiovascular system; Cells; Chronic; Data; Development; Diabetes Mellitus; Disease; Enzymes; Epigenetic Process; Faculty; Functional disorder; GLUT 4 protein; Gene Expression; Genetic; Genetic Models; Healthcare Systems; Homeostasis; Human; Hyperglycemia; Imiquimod; Impairment; Inflammation; Inflammatory; Interferon Type I; Interferons; JAK1 gene; Laboratories; Lead; Link; Literature; MLL gene; Macrophage; Mediating; Metabolic; Metabolic dysfunction; Methods; Molecular; Morbidity - disease rate; Mus; Myeloid Cells; Non-Insulin-Dependent Diabetes Mellitus; PPAR gamma; Patients; Phase; Phenotype; Process; Production; Psoriasis; Publishing; Regulation; Research; Research Personnel; Research Training; Risk; Risk Factors; Role; Running; STAT1 gene; STAT3 gene; Sequence Analysis; Signal Transduction; Skin; Skin Tissue; TNF gene; Techniques; Testing; Time; Tissue Sample; Tissues; Training; chronic inflammatory skin; cost; cytokine; experimental study; glucose metabolism; glycemic control; histone demethylase; histone methyltransferase; improved; keratinocyte; mortality; new therapeutic target; novel; overexpression; peripheral blood; pharmacologic; programs; skills; skin disorder; skin lesion; systemic inflammatory response; targeted treatment

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.

项目总结/摘要 最近的文献已经确定，银屑病，一种流行的慢性炎症性皮肤病，与 2型糖尿病（T2 D）的风险增加。这一点很重要，因为银屑病和T2 D的组合会恶化 血糖控制到更高的程度，导致继发性并发症的增加比任何一种疾病单独; 然而，银屑病患者易患T2 D的分子机制尚不清楚。在 银屑病，干扰素κ（IFNκ），一种I型IFN，在皮肤病变和外周血中增加，导致 全身炎症。我们的初步数据表明，组蛋白甲基转移酶，混合谱系白血病， 蛋白1（MLL 1）可以控制角质形成细胞中IFNκ的表达，这可能是由以下机制驱动的： Tyk 2/STAT 1信号传导。角质形成细胞过度表达IFNk与炎症反应增加有关。 皮肤和脂肪组织中的巨噬细胞（MΦs）和高血糖症的发展。为此，我们初步 数据表明，角质形成细胞来源的IFNκ可以通过JMJD 3- 中介机制。此外，我们的小组已经确定，JMJD 3，一种组蛋白去甲基化酶，在 调节皮肤中的炎性MΦ，并且在IFNκ/JAK 1/STAT 3刺激后在MΦ中上调。这 K99/R 00提案旨在检验Tyk 2/STAT 1信号转导上调角质形成细胞中MLL 1的假设 并且是银屑病中IFNκ过表达的机制基础。此外，我们认为，IFNκ的这种增加 银屑病角质形成细胞通过炎症途径驱动MΦ在皮肤和脂肪组织中走向炎症表型 JMJD 3介导的机制。这些炎症性脂肪组织巨噬细胞（ATM）然后驱动脂肪细胞 通过调节PPARγ和GLUT 4导致代谢功能障碍。为了验证这些假设，我们将继续 本奖项K99阶段的以下目标：目的1：确定MLL 1介导的机制， 银屑病组织中角质形成细胞IFNκ的表达受到调节，目的2：研究其机制， 角质形成细胞衍生的IFNκ调节银屑病中的MΦ表型在此期间，PI将接受研究 表观遗传学技术培训，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（R 00），她将确定机制 ATM衍生的TNFα通过其在银屑病中失调脂肪细胞葡萄糖代谢并确定IFNκ 抑制改善葡萄糖代谢（AIM 3）。K99阶段的拟议技术培训将 为PI提供必要的技能，以运行一个成功的独立研究项目，研究 慢性皮肤炎症疾病和代谢功能障碍之间的联系。