The role of DNA methylation in dysregulated monocyte immune responses during malnutrition and recovery

DNA甲基化在营养不良和恢复期间单核细胞免疫反应失调中的作用

• 批准号: 10437902
• 负责人: Kristen Mary Chossek Malecki
• 金额: $ 19.12万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437902
• 关键词: Aberrant DNA Methylation; Adult; Adverse effects; Affect; Anti-Inflammatory Agents; Biological Response Modifiers; Body Weight; Calories; Cardiometabolic Disease; Cause of Death; Cell Differentiation process; Cells; Cessation of life; Child; Childhood; Chronic Disease; Communicable Diseases; Complex; DNA; DNA Methylation; Data; Development; Diet; Dietary Intervention; Dietary Proteins; Disease Marker; Elements; Endotoxins; Enzymes; Epigenetic Process; Escherichia coli; Essential Amino Acids; Face; Food; Foundations; Future; Genes; Growth; Health; Height; Immune; Immune response; Immune system; Immunity; Immunologic Deficiency Syndromes; Impairment; Infection; Inflammatory; Innate Immune Response; Intake; Intervention; Link; Lipopolysaccharides; Long-Term Effects; Macrophage; Malignant Neoplasms; Malnutrition; Measures; Mediating; Mediation; Messenger RNA; Methylation; Milk; Modeling; Molecular; Morbidity - disease rate; Mus; Nature; Nutrient; Obesity; Outcome; Pathogen detection; Pathway interactions; Phenotype; Physiological; Physiology; Play; Predisposition; Production; Proteins; Recovery; Reduce health disparities; Role; Source; Spleen; Testing; United States; Weaning; Weight; Weight Gain; Wheat; Work; adaptive immune response; bisulfite sequencing; body system; cytokine; design; dietary; disorder risk; efficacy evaluation; experience; fetal; food insecurity; fortification; global health; immune function; improved; infection risk; insight; methylation pattern; monocyte; mortality; mouse model; multiple chronic conditions; novel; postnatal; response; transcription factor; transcriptomics; whole genome

Malnutrition, resulting from insufficient intake of calories or essential nutrients, is a persistent global health problem. In the United States, over 13 million children face food insecurity linked to malnutrition (usda.gov). Malnutrition is associated with significant morbidity and mortality and is responsible for more than 45% of all deaths in children younger than five years. Decreased immunity is a major health concern as infectious diseases are the leading cause of mortality among malnourished children. The long-term consequences of childhood malnutrition are increased rates of obesity, cardiometabolic disorders and cancer in adulthood, in which immune dysregulation may play an important role. However, the exact nature of immunodeficiency in malnutrition and the underlying mechanisms, particularly the role of epigenetics, are still not understood. In addition, most studies evaluating the efficacy of common dietary interventions for treating malnutrition focus on key anthropometric measures (height, weight) but rarely assess other markers of disease risk such as immune function. While altered immune function is a well-established consequence of malnutrition in childhood, underlying mechanisms are unknown. Therefore, there is a critical need for mechanistic studies to better understand the complex physiology of malnutrition and recovery in order to design more effective dietary interventions that would improve both short- and long-term health outcomes. This novel study specifically examines the role of DNA methylation in monocytes as key regulator of the immune response impacted by malnutrition. We will also look at how different protein sources, commonly used in treatment diets alters these mechanisms. This study builds on our own preliminary data which showed differences in altered immune function associated with different dietary interventions in mice. The first aim of the study will investigate how two weeks of protein malnutrition, induced by a low protein (5% protein calories) diet, in weaning mice affects the monocyte immune response elicited by bacterial endotoxin. To better understand mechanisms, we will explore altered DNA methylation patterns and associations with monocytes activities. DNA methylation will be assessed by whole-genome bisulfite sequencing. In the second aim, we will explore the efficacy of different treatment diets supplemented with wheat, milk or peanut proteins administered for six weeks after a two-week period of induced protein malnutrition. We will determine the impact of the different treatment diets on the recovery of immune responses and explore DNA methylation as molecular mechanism underlying differential effects of dietary proteins on monocyte responses to endotoxin. The study will lay the foundation for future research to understand opportunities to mitigate the long-term effects of childhood malnutrition on adult immune function and chronic disease.

营养不良是由于卡路里或必需营养素的摄入不足而导致的，这是一个持续存在的全球健康问题。在美国，超过1300万儿童面临与营养不良有关的粮食不安全（USDA.GOV）。营养不良与显着的发病率和死亡率有关，造成五岁以下儿童死亡的45％以上。免疫力下降是一个主要的健康问题，因为传染病是营养不良儿童死亡的主要原因。儿童营养不良的长期后果是成年期肥胖，心脏代谢疾病和癌症的率提高，其中免疫失调可能起重要作用。然而，仍然尚不清楚营养不良的免疫缺陷和基本机制，尤其是表观遗传学的作用的确切性质。此外，大多数研究评估了常见饮食干预措施治疗营养不良的功效，重点是关键的人体测量指标（身高，体重），但很少评估疾病风险的其他标志物，例如免疫功能。虽然免疫功能改变是童年营养不良的完善后果，但潜在的机制尚不清楚。因此，对于机械研究的迫切需要，可以更好地了解营养不良和恢复的复杂生理，以设计更有效的饮食干预措施，以改善短期和长期健康结果。这项新研究专门研究了DNA甲基化在单核细胞中的作用，作为营养不良影响的免疫反应的关键调节剂。我们还将研究治疗饮食中常用的不同蛋白质来源如何改变这些机制。这项研究以我们自己的初步数据为基础，该数据表明与小鼠不同饮食干预措施不同的免疫功能改变的差异。该研究的第一个目的将研究蛋白质营养不良的两周蛋白质营养不良是如何由低蛋白（5％蛋白质卡路里）饮食诱导的，在断奶小鼠中如何影响细菌内毒素引起的单核细胞免疫反应。为了更好地理解机制，我们将探索改变的DNA甲基化模式和与单核细胞活性的关联。 DNA甲基化将通过全基因组亚硫酸盐测序评估。在第二个目标中，我们将探索补充了两周诱导蛋白营养不良后六个星期的小麦，牛奶或花生蛋白的不同治疗饮食的功效。我们将确定不同的治疗饮食对免疫反应恢复的影响，并探索DNA甲基化，因为饮食蛋白对单核细胞对内毒素的反应的差异作用的分子机制。这项研究将奠定未来研究的基础，以了解机会减轻儿童营养不良对成人免疫功能和慢性疾病的长期影响。