Sex and gender differences in lupus - intersection between immunometabolism, epigenetic remodeling and cardiac involvement

狼疮的性别和性别差异——免疫代谢、表观遗传重塑和心脏受累之间的交叉

• 批准号: 10470275
• 负责人: Caroline Jefferies
• 金额: $ 58.25万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470275
• 关键词: Address; Affect; Angiography; Area; Autoimmune Diseases; Autoimmunity; Automobile Driving; CD14 gene; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Cholecalciferol; Chromatin; Coenzymes; Coronary; Coronary Arteriosclerosis; Data; Development; Disease; Drug Targeting; Epigenetic Process; FCGR3B gene; Female; Flow Cytometry; Functional disorder; Gender; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genetic; Genetic Transcription; Glycolysis; Imaging Techniques; Immune response; Immunization; Immunologic Memory; Inflammatory; Interferon Type I; Interferon-alpha; Interferons; Investigation; Isocitrate Dehydrogenase; Link; Lupus; Metabolic; Metabolic Pathway; Metabolism; Methods; Microvascular Dysfunction; Mitochondrial Proteins; Organ; Outcome; Oxidative Phosphorylation; Pathology; Pathway interactions; Patients; Phenotype; Play; Prevalence; Production; Proteomics; Publishing; Relative Risks; Research; Rheumatoid Arthritis; Risk; Role; Severity of illness; Sex Bias; Sex Differences; Sun Exposure; Symptoms; Systemic Lupus Erythematosus; Testing; Time; Viral; Virus Diseases; Vitamin D; Woman; XCL1 gene; base; cardiac magnetic resonance imaging; cardiovascular disorder risk; cardiovascular imaging; cytokine; disorder risk; extracellular; gender difference; gene regulatory network; heart imaging; high dimensionality; histone methylation; imaging approach; male; men; metabolomics; monocyte; next generation sequencing; oxidized low density lipoprotein; programs; response; sex; sexual dimorphism; single-cell RNA sequencing; systemic autoimmune disease

Lupus is predominantly a female disease, however men with lupus frequently have more severe symptoms and organ involvement including cardiovascular disease, a leading cause of death in lupus. Environmental and gender differences such as sunlight exposure and vitamin D levels have also been shown to play a role in lupus progression and cardiovascular disease. Differences in metabolic activity have also been suggested to contribute to sexually dimorphic immune responses and autoimmunity. Our recent data in female lupus combining cardiac imaging with metabolomic profiling has shown potential links between cardiac involvement and metabolic reprogramming of lupus monocytes. This proposal investigates the hypothesis that sex biases in metabolic activity of monocytes drives epigenetic reprogramming of monocytes, driving functional differences. Secondly, it will address how sexually dimorphic responses to vitamin D contribute to monocytic reprogramming. As epigenetic changes in monocytes is linked with cardiovascular disease (CVD), and given the prevalence of CVD in both male and female lupus, this proposal will address whether sex-specific changes in metabolic and genetic reprogramming drive phenotypic differences in lupus monocytes and ask how this relates to prevalence of CMD and CVD using state of the art cardiac imaging. Aim 1: Determine whether metabolic pathways differ in monocytes from male and female lupus patients. We will address how sexual dimorphism in immune responses and immunometabolism in monocytes integrate to affect outcome between male and female patients using metabolic, proteomic and flow cytometry approaches. Aim 2: Determine how genetic reprogramming drives sexually dimorphic monocytic function in lupus. Single cell next generation sequencing will be used to determine chromatin accessibility in monocyte subsets and ask how this influences gene expression programs and functional differences in male and female lupus. Aim 3: Assess relative risk of CVD in male lupus using non-invasive cardiac imaging techniques. Cardiac imaging will determine prevalence of CVD in male and female lupus and correlated with metabolic changes or gene expression patterns to determine sexually dimorphic responses that determine risk. Impact: Determining whether metabolic reprograming and epigenetic remodeling are sexually dimorphic in lupus monocytes will potentially impact treatment approaches as we enter an era where drugs targeting immunometabolism as being trialed in lupus.

狼疮主要是一种女性疾病，但患有狼疮的男性通常会出现更严重的症状， 器官受累，包括心血管疾病，这是狼疮死亡的主要原因。环境和 阳光照射和维生素 D 水平等性别差异也被证明与狼疮有关 进展和心血管疾病。代谢活动的差异也被认为有助于 性二态性免疫反应和自身免疫。我们最近关于女性狼疮合并心脏病的数据 代谢组学成像显示心脏受累与代谢之间的潜在联系 狼疮单核细胞的重编程。该提案调查了代谢中性别偏见的假设 单核细胞的活性驱动单核细胞的表观遗传重编程，从而驱动功能差异。其次，它 将探讨维生素 D 的性二态性反应如何促进单核细胞重编程。作为 单核细胞的表观遗传变化与心血管疾病 (CVD) 有关，并且考虑到 CVD 的患病率 在男性和女性狼疮中，该提案将解决代谢和遗传方面的性别特异性变化是否 重编程驱动狼疮单核细胞的表型差异，并探讨这与 CMD 患病率有何关系 和使用最先进的心脏成像的 CVD。 目标 1：确定男性和女性狼疮患者单核细胞的代谢途径是否不同。 我们将讨论单核细胞免疫反应和免疫代谢中的性别二态性如何整合 使用代谢、蛋白质组学和流式细胞术方法影响男性和女性患者的结果。 目标 2：确定基因重编程如何驱动狼疮中的性二态性单核细胞功能。 单细胞下一代测序将用于确定单核细胞亚群中染色质的可及性 并询问这如何影响男性和女性狼疮的基因表达程序和功能差异。 目标 3：使用非侵入性心脏成像技术评估男性狼疮的 CVD 相对风险。 心脏成像将确定男性和女性狼疮中 CVD 的患病率，并与代谢相关 变化或基因表达模式来确定决定风险的性二态性反应。 影响：确定狼疮中的代谢重编程和表观遗传重塑是否存在性别二态性 当我们进入一个药物靶向的时代时，单核细胞可能会影响治疗方法 免疫代谢正在狼疮中进行试验。