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Principal Investigator: Robert J Freishtat
Organization: CHILDREN'S RESEARCH INSTITUTE
Fiscal Year: 2019
Award: $188,112
Funding agency: John E. Fogarty International Center for Advanced Study in the Health Sciences
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.
Terms: <21+ years old><Adipocytes><Adipose Cell><Adipose tissue><Adult><Adult Human><Assay><Automobile Driving><Back><Big Baby><Bioassay><Biologic Assays><Biological Assay><Birth><Birthweight High><Body Composition><Body Fluids><Body fat><Capital><Cells Placenta-Tissue><Chronic><Clinical Data><Collaborations><Cord Blood><Cyanocobalamin><DEXA><DXA><Data><Development><Diabetes Mellitus><Diagnostic><Disease><Disorder><Dorsum><Dual-Energy X-Ray Absorptiometry><Endocytic Vesicle><Endocytotic Vesicle><Environmental Exposure><Fat Cells><Fats><Fatty Tissue><Fatty acid glycerol esters><Foundations><Funding><Gene Expression><Gestation><Goals><Heavy baby><High Prevalence><High birth weight baby><High birth weight infant><High birthweight baby><Home><Home environment><Hospitals><India><Individual><Infant><Infant Large><Injury><Insulin Resistance><International><Investigators><Large baby><Large baby for gestational age><Large birth weight><Leanness><Length of Life><Life><Lipocytes><Long-term cohort study><Longevity><Longitudinal cohort study><Longterm cohort study><Low Birth Weight Infant><Malnutrition><Mature Lipocyte><Mature fat cell><Measures><Mediator><Mediator of Activation><Mediator of activation protein><Metabolic><Micro RNA><MicroRNAs><Molecular><Molecular and Cellular Biology><Multi-center studies><Multicenter Studies><NIH><National Institutes of Health><Normal Placentoma><Nutritional Deficiency><Obesity><Parturition><Pathogenesis><Pathway interactions><Patients><Phenotype><Placenta><Placenta Embryonic Tissue><Placentome><Pregnancy><Preventative strategy><Prevention strategy><Preventive strategy><Primary Prevention><Research><Research Personnel><Research Proposals><Research Support><Researchers><Risk><STAT3><STAT3 gene><Signal Pathway><Techniques><Testing><Thinking><Thinness><Translational Research Enterprise><Umbilical Cord Blood><Undernutrition><United States><United States National Institutes of Health><VIT B12><Visit><Vitamin B 12><Vitamin B 12 Deficiency><Vitamin B12><Vitamin B12 Deficiency><adipogenesis><adipose><adiposity><adult adiposity><adult obesity><adulthood><adults with obesity><biobank><biorepository><cardiometabolic><cardiometabolism><child adiposity><child obesity><childhood adiposity><childhood obesity><cohort><corpulence><corpulency><corpulentia><developmental><diabetes><diabetes risk><diabetic><dietary deficiency><disease prevention><disorder prevention><driving><excessive Fetal growth><exosome><fetal><fetal adiposity><fetal cord blood><glucose tolerance><high risk><implementation strategy><infancy><infant adiposity><infantile><insulin resistant><intergenerational><knowledge base><knowledgebase><life span><lifespan><lipid biosynthesis><lipogenesis><low birth weight><low birth weight infant human><low birthweight><malnourished><maternal adiposity><maternal obesity><meetings><member><miRNA><miRNAs><nano particle><nano-sized particle><nanoparticle><nanosized particle><novel><nutrition deficiency><nutrition deficiency disorder><nutritional deficiency disorder><obese><obese children><obese people><obese person><obese population><obesity during childhood><obesity in children><offspring><pathway><pediatric obesity><peripheral blood><programs><prospective><therapeutic target><thoughts><translation research enterprise><translational research program><treatment strategy><white adipose tissue><yellow adipose tissue>