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.

项目摘要/摘要 最近的文献已经确定，牛皮癣是一种普遍的慢性炎性皮肤疾病，与 2型糖尿病（T2D）的风险增加。这很重要，因为牛皮癣和T2D的组合担忧 血糖控制在更大程度上，导致继发并发症的增加比单独的任何一种疾病。 但是，易患牛皮癣患者发育T2D的分子机制尚不清楚。 牛皮癣，干扰素Kappa（IFNκ），I型IFN，在皮肤病变和外周血中增加了 系统性炎症。我们的初步数据确定了组蛋白甲基转移酶混合谱系白血病 蛋白1（MLL1），可以控制角质形成细胞中的IFNκ表达，这可能是由机械驱动的 TYK2/STAT1信号传导。角质形成细胞对IFNK的这种过表达与炎症增加有关 皮肤和脂肪组织和高血糖发育的巨噬细胞（MφS）。为此，我们的初步 数据确定角质形成细胞衍生的IFNκ可以通过JMJD3-驱动Mφ向炎症表型推动Mφ 中介机制。此外，我们的小组已经确定JMJD3是一种组蛋白脱甲基酶，在 调节皮肤中的炎症Mφ，并在IFNκ/JAK1/STAT3刺激后在Mφ中进行更新。这 K99/R00建议旨在检验Tyk2/STAT1信号传导上调角质形成细胞中MLL1的假设 并在机械上使牛皮癣中的IFNκ过表达基础。此外，我们建议这增加IFNκ 通过银屑病的角质形成细胞将Mφ通过A驱动Mφ朝着皮肤和脂肪组织中的炎症表型驱动 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的代谢功能障碍。为了检验这些假设，我们将追求 以下在本奖项的K99阶段的目标：目标1：确定MLL1介导的机制 角质形成细胞IFNκ表达在牛皮癣组织中受到调节，目标2：检查机制 角质形成细胞衍生的IFNκ调节牛皮癣中的Mφ表型。在此期间，PI将获得研究 对表观遗传技术的培训，隔离和培养人角质形成细胞，序列分析和隔离 来自脂肪组织的巨噬细胞。在独立阶段（R00）中，她将确定机制 ATM衍生的TNFα在牛皮癣中的脂肪细胞代谢失调，并确定IFNκ是否是否 抑制作用改善了葡萄糖代谢（AIM 3）。在K99阶段提议的技术中的培训将 负担PI的必要技能，以成功地研究关系的独立研究计划 在慢性皮肤感染疾病和代谢功能障碍之间。