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，但是狼疮的男性经常出现更严重的症状，并且 器官受累，包括心血管疾病，这是狼疮的主要死亡原因。环境和 性别差异（例如阳光暴露和维生素D水平）也已显示出在狼疮中发挥作用 进展和心血管疾病。还建议代谢活性的差异有助于 性二态免疫反应和自身免疫性。我们最近在雌性狼疮的数据结合心脏的数据 代谢组分析的成像显示了心脏参与与代谢之间的潜在联系 狼疮单核细胞的重编程。该提案调查了一个假设，即性别偏见代谢 单核细胞的活性驱动单核细胞的表观遗传重编程，驱动功能差异。其次，它 将解决对维生素D的性二态反应有助于单核细胞重编程。作为 单核细胞的表观遗传变化与心血管疾病（CVD）有关，并且鉴于CVD的患病率 在男性和雌性狼疮中，该提案将解决特定性别的代谢和遗传变化 重编程驱动狼疮单核细胞的表型差异，并询问这与CMD的患病率有何关系 和CVD使用最先进的心脏成像。 目标1：确定单核细胞与雄性狼疮患者的单核细胞的代谢途径是否不同。 我们将解决单核细胞中免疫反应和免疫代谢中的性二态性 使用代谢，蛋白质组学和流式细胞仪方法影响男性和女性患者之间的结果。 目标2：确定遗传重编程如何驱动狼疮中性二态单核的功能。 单细胞下一代测序将用于确定单核细胞子集中的染色质可及性 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。 AIM 3：使用非侵入性心脏成像技术评估雄性狼疮中CVD的相对风险。 心脏成像将确定男性和雌性狼疮中CVD的患病率，并与代谢相关 改变或基因表达模式以确定确定风险的性二态反应。 影响：确定代谢重编程和表观遗传重塑是否在狼疮中是性二态的 当我们进入靶向药物的时代时，单核细胞可能会影响治疗方法 免疫代谢为在狼疮中被试用。