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

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 印度是世界上糖尿病患病率最高的国家（2015 年有 7100 万患者），也是糖尿病患者的故乡。 乍一看，低出生体重 (LBW) 婴儿的数量最多（每年 6-800 万）。 然而，出生体重与成年后患糖尿病的最终风险之间往往存在关联。 被描述为“U 形”（即低出生体重和高出生体重都会增加个体成年糖尿病的风险）。 与直觉相反，印度低出生体重婴儿出生时脂肪含量较高（即体脂百分比），即所谓的“瘦脂肪” 印度悖论。”这归因于影响胎儿大小和身体成分的多种因素，包括 母亲的瘦胖表型、营养不良和血糖这些低出生体重婴儿面临着高风险。 成人肥胖和心脏代谢疾病的发展。 婴儿）的影响被怀疑是造成这种风险的一个新的可能性是与肥胖相关的母亲。 PIs 团队最近通过胎盘重新编程胎儿心脏代谢发育途径。 确定脂肪细胞衍生的外泌体是能够驱动胎儿心脏代谢异常的母体因素 发育并已知是肥胖儿童和心脏代谢疾病的器官间介质 作为纳米颗粒大小的内吞囊泡，这些外泌体可以穿过胎盘及其 microRNA。 因为我们开发了技术来改变发育途径的基因表达。 从体液中分离这些外泌体，我们此应用的总体目标是测试这种关联 在现有研究的基础上，研究母体脂肪细胞衍生的外泌体与婴儿肥胖症之间的关系 我们将通过使用临床数据和在印度进行前瞻性多中心研究的能力来实现这一目标。 来自印度母婴对的生物样本是队列纵向研究的一部分（当前 n = 288） 印度浦那爱德华国王纪念医院的美印团队为此生成了初步数据。 PI 最近访问印度期间的应用 我们的中心假设是孕产妇和婴儿的水平下降。 靶向脂肪生成的脐带血脂肪细胞衍生的外泌体 microRNA 与婴儿高体重相关 事实上，我们的初步数据支持母亲肥胖/肥胖会抑制 microRNA 靶向脂肪生成途径成员，因此预计会导致胎儿脂肪生成增加。 该研究团队由 NIH 和印度资助的研究人员组成，他们在所有领域都具有国际专业知识 队列生物样本库的丰富性是这种不断发展的合作的重要资产。 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）：“支持当地相关的催化试点研究”； “支持我们的长期诊断、预防、治疗和实施策略的制定。” 目标是改变目前对儿童肥胖和心脏代谢发病机制的认识 此外，该项目可能会确定一级预防的潜在治疗靶点。 印度和美国的这些疾病，为更全面的研究奠定了基础 丰富知识库并向 NIH 和其他机构提出更多研究提案的计划 来自美国和印度团队的资助者。