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.

项目概要/摘要 最近的文献表明，牛皮癣是一种流行的慢性炎症性皮肤病，与 患 2 型糖尿病 (T2D) 的风险增加，这一点很重要，因为银屑病和 T2D 的结合会恶化。 与单独任何一种疾病相比，更大程度地控制血糖，导致继发并发症增加； 然而，银屑病患者易患 T2D 的分子机制尚不清楚。 银屑病时，干扰素 kappa (IFNκ)（一种 I 型干扰素）在皮损和外周血中增加，导致 我们的初步数据表明，混合谱系白血病是一种组蛋白甲基转移酶。 蛋白 1 (MLL1) 可能控制角质形成细胞中的 IFNκ 表达，这可能是由以下机制驱动的 Tyk2/STAT1 信号转导通过角质细胞过度表达 IFNk 与炎症增加相关。 为此，我们初步研究了皮肤和脂肪组织中的巨噬细胞（MΦs）与高血糖的发展。 数据表明，角质形成细胞衍生的 IFNκ 可以通过 JMJD3- 驱动 MΦ 产生炎症表型 此外，我们的研究小组还发现，JMJD3（一种组蛋白去甲基化酶）在调节机制中发挥着至关重要的作用。 调节皮肤中的炎症 MΦ，并且在 IFNκ/JAK1/STAT3 刺激后 MΦ 上调。 K99/R00 提案旨在检验 Tyk2/STAT1 信号传导上调角质形成细胞中 MLL1 的假设 并且从机制上讲，这是银屑病中 IFNκ 过度表达的基础。此外，我们提出 IFNκ 的增加。 银屑病角质形成细胞通过 JMJD3 介导的机制随后这些炎症脂肪组织巨噬细胞 (ATM) 驱动脂肪细胞。 通过 PPARγ 和 GLUT4 的调节导致代谢功能障碍 为了检验这些假设，我们将进行以下研究。 该奖项 K99 阶段的以下目标： 目标 1：确定 MLL1 介导的机制，通过该机制 角质形成细胞 IFNκ 表达在银屑病组织中受到调节，目标 2：检查其机制 角质细胞衍生的 IFNκ 调节银屑病的 MΦ 表型 在此期间，PI 将接受研究。 表观遗传技术、分离和培养人类角质形成细胞、序列分析和分离方面的培训 在独立阶段（R00），她将确定来自脂肪组织的巨噬细胞的机制。 ATM 衍生的 TNFα 通过调节银屑病中的脂肪细胞葡萄糖代谢并确定 IFNκ 是否 抑制可改善葡萄糖代谢（AIM 3）。在 K99 阶段进行所提出的技术培训。 为 PI 提供必要的技能来开展成功的独立研究项目，研究这种关系 慢性皮肤炎症疾病与代谢功能障碍之间的关系。