Maternal Adipocyte-Derived Exosomes in the Thin-Fat Indian Baby Paradox

印度婴儿瘦子悖论中母体脂肪细胞衍生的外泌体

• 批准号: 9766906
• 负责人: Robert J Freishtat
• 金额: $ 18.81万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766906
• 关键词: Adipocytes; Adipose tissue; Adult; Automobile Driving; Back; Biological Assay; Birth; Body Composition; Body Fluids; Body fat; Capital; Chronic; Clinical Data; Collaborations; Data; Development; Diabetes Mellitus; Diagnostic; Disease; Dual-Energy X-Ray Absorptiometry; Endocytic Vesicle; Environmental Exposure; Fatty acid glycerol esters; Foundations; Funding; Gene Expression; Goals; High Prevalence; High birth weight infant; Home environment; Hospitals; India; Individual; Infant; Injury; Insulin Resistance; International; Life; Longevity; Longitudinal cohort study; Low Birth Weight Infant; Malnutrition; Measures; Mediator of activation protein; Metabolic; MicroRNAs; Molecular; Molecular and Cellular Biology; Multicenter Studies; Obesity; Pathogenesis; Pathway interactions; Patients; Phenotype; Placenta; Pregnancy; Prevention strategy; Primary Prevention; Research; Research Personnel; Research Proposals; Research Support; Risk; STAT3 gene; Signal Pathway; Techniques; Testing; Thinking; Thinness; Umbilical Cord Blood; United States; United States National Institutes of Health; Visit; Vitamin B 12; Vitamin B 12 Deficiency; adult obesity; biobank; cardiometabolism; cohort; diabetes risk; diabetic; disorder prevention; exosome; fetal; glucose tolerance; high risk; implementation strategy; infancy; infant adiposity; intergenerational; knowledge base; lipid biosynthesis; maternal obesity; meetings; member; nanoparticle; novel; obesity in children; offspring; peripheral blood; programs; prospective; therapeutic target; translational research program; treatment strategy; Adipocytes; Adipose tissue; Adult; Automobile Driving; Back; Biological Assay; Birth; Body Composition; Body Fluids; Body fat; Capital; Chronic; Clinical Data; Collaborations; Data; Development; Diabetes Mellitus; Diagnostic; Disease; Dual-Energy X-Ray Absorptiometry; Endocytic Vesicle; Environmental Exposure; Fatty acid glycerol esters; Foundations; Funding; Gene Expression; Goals; High Prevalence; High birth weight infant; Home environment; Hospitals; India; Individual; Infant; Injury; Insulin Resistance; International; Life; Longevity; Longitudinal cohort study; Low Birth Weight Infant; Malnutrition; Measures; Mediator of activation protein; Metabolic; MicroRNAs; Molecular; Molecular and Cellular Biology; Multicenter Studies; Obesity; Pathogenesis; Pathway interactions; Patients; Phenotype; Placenta; Pregnancy; Prevention strategy; Primary Prevention; Research; Research Personnel; Research Proposals; Research Support; Risk; STAT3 gene; Signal Pathway; Techniques; Testing; Thinking; Thinness; Umbilical Cord Blood; United States; United States National Institutes of Health; Visit; Vitamin B 12; Vitamin B 12 Deficiency; adult obesity; biobank; cardiometabolism; cohort; diabetes risk; diabetic; disorder prevention; exosome; fetal; glucose tolerance; high risk; implementation strategy; infancy; infant adiposity; intergenerational; knowledge base; lipid biosynthesis; maternal obesity; meetings; member; nanoparticle; novel; obesity in children; offspring; peripheral blood; programs; prospective; therapeutic target; translational research program; treatment strategy

Abstract India has the highest prevalence of diabetes in the world (71 million patients in 2015) and is home to the largest number of low birth weight (LBW) infants (6-8 million per year). At first glance, these may seem unrelated. However, the association between birthweight and eventual risk of diabetes as an adult is often described as “U-shaped” (i.e. both low and high birthweight increase adult diabetes risk for an individual). Counterintuitively, Indian LBW infants have high adiposity (i.e. percent body fat) at birth - the so-called “thin-fat Indian paradox.” This is ascribed to multiple factors which influence fetal size and body composition, including a maternal thin-fat phenotype, undernutrition, and glycemia. These LBW infants are at high risk for development of adult adiposity and cardiometabolic diseases. Intergenerational and early life (i.e. fetal and infantile) influences are suspected to underlie this risk. A novel possibility is that an adiposity-related maternal factor crosses the placenta to reprogram fetal cardiometabolic developmental pathways. The PIs team recently identified adipocyte-derived exosomes as a maternal factor capable of driving abnormal fetal cardiometabolic development and known to be an interorgan mediator of cardiometabolic diseases in obese children and adults. As nanoparticle-sized endocytic vesicles, these exosomes can cross the placenta and their microRNA contents are predicted to alter developmental pathway gene expression. Because we developed techniques to isolate these exosomes from body fluids, our overall objective for this application is to test the association between maternal adipocyte-derived exosomes and infant adiposity while building upon existing research capacity for a prospective multicenter study in India. We will achieve this objective by using clinical data and biospecimens from Indian maternal-infant pairs that are part of a longitudinal cohort study (current n=288) led at King Edward Memorial Hospital, Pune, India. The US-Indian team generated preliminary data for this application during a recent visit by the PI to India. Our central hypothesis is that reduced levels of maternal and cord blood adipocyte-derived exosomal microRNAs that target adipogenesis are associated with high infant adiposity. Indeed, our preliminary data support that maternal adiposity/obesity suppresses microRNAs that target adipogenesis pathway members and therefore are predicted to result in increased fetal adipogenesis. The research team is comprised of NIH- and Indian-funded investigators with international expertise in all relevant fields. The richness of the cohort biorepository is a major asset to this evolving collaboration. The study matches well with the goals indicated by the PAR-16-052 - Global Noncommunicable Diseases and Injury across the Lifespan: Exploratory Research (R21): “Support locally-relevant and catalytic pilot research”; and “Support development of diagnostics, prevention, treatment and implementation strategies.” Our long-term goal is to transform current thinking about the pathogenesis of childhood adiposity and cardiometabolic diseases. Moreover, the project is likely to identify potential therapeutic targets for the primary prevention of these diseases in India and the United States, laying the foundation for more a comprehensive research program that enriches the knowledge base and leads to additional research proposals to the NIH and other funders from this US and Indian team.

抽象的 印度的糖尿病患病率最高（2015年为7100万患者），是该糖尿病 最大的低出生体重（LBW）婴儿（每年6-8百万）。乍一看，这些似乎 无关。但是，成年人的出生体重和最终糖尿病风险之间的关联通常是 被描述为“ U形”（即低出生和高出生体重增加成人糖尿病的风险）。 违反直觉，印度LBW婴儿出生时具有高脂肪（即体内脂肪百分比） - 所谓的“薄脂肪” 印度悖论。“这分配给了影响胎儿大小和身体成分的多种因素 主要的薄脂肪表型，营养不良和糖脂症。这些LBW婴儿有高风险 成人肥胖和心脏代谢疾病的发展。代际和早期生活（即胎儿和 怀疑婴儿的影响是这种风险的基础。一种新颖的可能性是与肥胖相关的母体 因子穿过心plapeta以重编程胎儿心脏代谢发育途径。 PIS团队 确定脂肪细胞衍生的外泌体是能够驱动异常胎儿心脏代谢的主要因素 发育，被称为肥胖儿童心脏代谢疾病的组织间介质 成年人。作为纳米颗粒大小的内吞蔬菜，这些外泌体可以穿越多余的microRNA 预测含量会改变发育途径基因表达。因为我们开发了技术 将这些外泌体与体液分离，我们的总体目标是测试关联 在现有研究的基础上，在孕产妇脂肪细胞衍生的外泌体和婴儿肥胖之间 印度一项前瞻性多中心研究的能力。我们将通过使用临床数据和 来自印度产妇对的生物测量是纵向队列研究的一部分（当前n = 288）LED 在印度浦那国王爱德华纪念医院。美国 - 印度团队为此生成了初步数据 PI最近访问印度的申请。我们的核心假设是，孕产妇和 靶向脂肪生成的脐带血脂肪细胞衍生的外泌体microRNA与婴儿高有关 肥胖。实际上，我们的初步数据支持母体肥胖/肥胖症抑制了microRNA 靶脂肪形成途径成员，因此预计会导致胎儿脂肪形成增加。 研究小组已完成由NIH和印度资助的调查员，拥有国际专业知识 相关字段。队列生物座席的丰富性是这种不断发展的合作的主要资产。这 研究与PAR-16-052-全球非传染性疾病和 整个生命周期的伤害：探索性研究（R21）：“支持与当地与催化试验研究的支持”； 以及“支持诊断，预防，治疗和实施策略的开发”。我们的长期 目标是改变有关儿童肥胖和心脏代谢的发病机理的当前思考 疾病。此外，该项目可能会确定主要预防的潜在治疗靶标 这些疾病在印度和美国，为更多全面研究奠定了基础 丰富知识基础并为NIH和其他的其他研究建议的计划 来自美国和印度团队的资助者。