Extracellular vesicle cargo and risk of NAFLD and NASH in Latino youth

拉丁裔青年的细胞外囊泡负载以及 NAFLD 和 NASH 的风险

基本信息

批准号：
10446517
负责人：
Johanna K DiStefano
金额：
$ 85.2万
依托单位：
TRANSLATIONAL GENOMICS RESEARCH INST
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10446517
关键词：
Address Adolescent Adult Affinity Age Apoptosis Biological Biopsy Body mass index Cardiovascular Diseases Caring Cell Communication Cells Cellular biology Cessation of life Characteristics Child Childhood Complement Development Diabetes Mellitus Diagnostic Discriminant Analysis Disease Disease Marker Economic Burden FDA approved Fatty Liver Fatty acid glycerol esters Future Gastrectomy Health Hepatic Hepatic Stellate Cell Hepatocyte Histopathologic Grade Individual Intervention Investigation Knowledge Latino Latino Population Life Life Style Lipids Liver Magnetic Resonance Imaging Measures Mediating Medical Membrane Membrane Proteins Methods Modality Modeling Molecular Morbidity - disease rate Non-Insulin-Dependent Diabetes Mellitus Nucleic Acids Obesity Outcome Pathogenesis Pathologic Patients Pattern Phenotype Pilot Projects Plasma Population Prevalence Prevention strategy Proteins Proteomics RNA Receptor Activation Research Resolution Risk Role Sampling Series Severities Severity of illness Shotguns Signal Transduction Surface Technology Testing Therapeutic Tissues Work Youth accurate diagnosis bariatric surgery base burden of illness cell type chronic liver disease clinically significant cohort drug development effective therapy experience experimental study extracellular vesicles high risk improved injury and repair innovation insight intercellular communication lifestyle intervention liver transplantation liver-specific protein macrophage migration mortality new therapeutic target non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel diagnostics pediatric non-alcoholic fatty liver disease response response to injury sex tissue injury transdifferentiation treatment strategy vesicular release

项目摘要

PROJECT SUMMARY/ABSTRACT The prevalence of pediatric nonalcoholic fatty liver disease (NAFLD) is escalating in US youth, particularly in those of Latino ancestry. NAFLD in children is associated with poor long-term outcomes, including diabetes, cardiovascular disease, and higher liver-related morbidity and mortality in adulthood. Despite the clinical significance of pediatric NAFLD, the mechanisms underlying its pathogenesis are poorly understood. This lack of knowledge is a major obstacle to the development of effective treatment and prevention strategies. Emerging studies support a role for extracellular vesicles (EVs) in NAFLD. Circulating EVs can influence intracellular signaling, tissue injury and repair, and matrix remodeling in liver cells. Plasma EV levels discriminate between adult patients with NAFLD and nonalcoholic steatohepatitis (NASH), and are positively correlated with histological grade. We conducted a series of proof-of-principle studies that demonstrate: 1) distinctive protein signatures in plasma EVs isolated from Latino children with NAFLD, 2) NAFLD-specific signatures approximate non-NAFLD signatures following lifestyle intervention that reduced liver fat, and 3) isolation of hepatocyte- specific EVs showed enrichment of liver-specific proteins in NAFLD. To date, however, investigations of EVs in pediatric NAFLD are scarce, and the role of EV-derived cargo in NAFLD pathogenesis in youth remains unknown. Here we propose a strategy to characterize the biological role of EVs in pediatric NAFLD. In Aim 1, we will apply unbiased methods to study proteins and RNAs carried in circulating and hepatocyte-enriched EVs to derive characteristic signatures associated with NAFLD and NASH in Latino youth. In Aim 2, we will measure EV concentration and content in youth with NAFLD who experienced changes in hepatic fat fraction following two distinct intervention modalities (i.e., intensive lifestyle and bariatric surgery). Importantly in Aim 3, we propose a series of molecular experiments to obtain mechanistic insight into the functional aspects of EV cargo. The combination of these approaches is innovative; and the strategy comprises a novel and sequentially appropriate set of aims that has not previously been used to address potential mechanisms of pathogenesis in pediatric NAFLD. The focus on children is especially impactful due to the growing prevalence of NAFLD in this population, the association of pediatric NAFLD with poor health outcomes in adulthood, and the expected future economic burden to care for these individuals. The focus on Latino children as an underrepresented yet growing population demographic is critical, because at every stage of life and along the entire NAFLD spectrum, Latinos experience a disproportionate burden of disease. The identification of EV-derived cargo associated with pediatric NAFLD will enhance our understanding of the biological mechanisms contributing to disease pathogenesis, provide a means to improve diagnostic and therapeutic strategies, and identify new targets for potential drug development.

项目摘要/摘要小儿非酒精性脂肪肝疾病（NAFLD）的患病率在美国青年中升级拉丁裔血统的人。儿童的NAFLD与包括糖尿病在内的长期结局不佳有关心血管疾病，成年后与肝脏相关的发病率和死亡率更高。尽管有临床小儿NAFLD的意义，其发病机理的基础机制知之甚少。这个缺乏知识是发展有效治疗和预防策略的主要障碍。新兴研究支持NAFLD中细胞外囊泡（EV）的作用。循环电动汽车会影响细胞内信号传导，组织损伤和修复，以及肝细胞中的基质重塑。等离子体EV水平区分 NAFLD和非酒精性脂肪性肝炎（NASH）的成年患者，与组织学等级。我们进行了一系列的原则研究，这些研究证明了：1）独特的蛋白质与NAFLD的拉丁裔儿童隔离的等离子体EV中的签名，2）NAFLD特异性签名近似生活方式干预后的非NAFLD签名减少了肝脏脂肪，3）肝细胞分离特定的电动汽车显示NAFLD中肝特异性蛋白的富集。但是，迄今为止，对电动汽车的调查小儿NAFLD稀缺，EV衍生的货物在NAFLD发病机理中的作用仍然未知。在这里，我们提出了一种表征电动汽车在小儿NAFLD中的生物学作用的策略。在AIM 1中，我们将申请无偏见的方法来研究循环和肝细胞富含电动汽车的蛋白质和RNA 拉丁裔青年中与Nafld和Nash相关的特征签名。在AIM 2中，我们将衡量EV NAFLD年轻人的集中和内容，在两次之后经历了肝脂肪分数的变化独特的干预方式（即强化生活方式和减肥手术）。重要的是在AIM 3中，我们建议一系列分子实验，以获取对EV货物功能方面的机械洞察力。这这些方法的结合是创新的。该策略包括一个新颖的，依次适当的以前尚未用于解决小儿发病机理的一组目标 nafld。由于NAFLD在这个人群中的普遍性日益普及，对儿童的关注尤其有影响力，小儿NAFLD与成年后健康状况不佳的协会以及预期的未来经济负担照顾这些人。关注拉丁裔儿童是人口不足但人口增长人群至关重要，因为在生活的每个阶段以及整个NAFLD范围内，拉丁裔经验疾病负担不成比例。与儿科NAFLD相关的EV衍生货物的识别将增强我们对导致疾病发病机理的生物学机制的理解，提供改善诊断和治疗策略的手段，并确定潜在药物开发的新目标。