Childhood obesity represents a major public health challenge. Growing evidence supports an important role for intrau-? terine conditions in shaping susceptibility for obesity (the fetal origins concept). However, many key questions remain regardingdeterminants,outcomesandunderlyingmechanisms.First,althoughmaternalmetabolicandstresshormones haveseparatelybeenidentifiedaskeybiologicaleffectorsoffetalprogramming,theirinteractionhasnotyetbeenexam-? ined in this context. Second, although it?s well established that it is not BMI, per se, but excess fat mass and its relative distribution(intra-?abdominal,hepatic)thatunderliesthedetrimentaleffectsofobesity,itisnotyetknownwhetherfetal programming influences the distribution of adipose tissue mass. Third, although mitochondrial function-?the central modulatorofcellularenergyproduction,storageanduse-?hasbeenidentifiedasakeymediatoroftheeffectsof insulin-? resistance (IR) and stress/cortisol on the development and pathogenesis of obesity, its role as a putative mechanism in fetal programming has yet to be determined. Dr. Lauren Gyllenhammer?s K99/R00 proposal addresses these 3 knowledge gaps using complementary designs (observational and experimental), state-?of-?the-?art methods (Magnetic Resonance(MR)andDualEnergyX-?RayAbsorptiometry(DXA)imaging),andmultiplelevelsofanalysis(cellstoinvivo physiology),totestthehypothesisthatmaternalprenatalstress/cortisolpotentiatestheunfavorableeffectsofgestational IRonoffspringadiposetissuemass/distribution,mediatedbyoffspringmitochondrialfunction.IntheK99mentoredphase, Dr.GyllenhammerwillleverageandaddmeasurestoanongoingNIH-?fundedprenatalobservationalcohort,withexisting maternalprenatalcortisolandfastingmetabolicmeasuresandoffspringserial %fatmassmeasures(DXAfrombirthto 5yrs) in N=100 mother/child dyads. She will add novel measures of MR-?based adipose tissue distribution and mito-? chondrialfunctioninthe5yroldchildren,andexaminethestatisticalinteractionbetweenmaternalcortisolandfasting markersofIRontheseoutcomes.Shewilladvanceherknowledgeoffetalprogramming,gestational/developmentalbi-? ology,andobtainadvancedbenchandanalysistechniquesrelevantforDOHaDresearch(cellularbiology/mitochondria bench training, bioinformatics analysis methods, cutting-?edge MRI methods in newborns and young children) through investigation of these aims, extensive hands-?on training, conferences, didactic instruction, and guidance from a diverse advisorycommitteeofrespectedresearchers.IntheR00phase,shewillenrollanew,independentcohortofN=80preg-? nantwomenanduseanexperimentalcross-?overstudydesigntoquantifythephysiologicalinteractionofprenatalstress andIRtoprospectivelypredictnewbornmitochondrialfunctionandadiposemassanddistributiontrajectoryfrombirth till6moage.ByutilizingtrainingfromtheK99phase,shewillexplorenovelcellularmechanismsofprenatalprogram-? ming, and uncover relationships between maternal prenatal psychological and metabolic stress on offspring adiposity development.Findingsfromthesecomplementarystudieswillimprovetheunderstandingofearlyriskfactorsforchild-? hood obesity, potentially provide cellular and behavioral interventional targets for prevention and treatment, and will furtherDr.Gyllenhammer?scareergoaltodevelopandestablishherselfasanindependentinvestigator.

Public Health Relevance

TheoverallgoalofthisapplicationistoprovideDr.LaurenGyllenhammersupportandprotectedtimeforanintensive, supervised career development experience in the biomedical, and developmental sciences, leading to research inde-? pendence. Based on a rigorous research question and methodology she has developed, Dr. Gyllenhammer will conduct trans-?disciplinaryresearchtoinvestigatethepotentialformaternalprenatalstresstopotentiatetheeffectsofmaternal insulin resistance on the development of offspring adiposity and mitochondrial health. This application describes her academicbackground,trainingactivities,researchstrategyandcareerdevelopmentplan.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Career Transition Award (K99)
Project #
1K99HD097302-01
Application #
9646707
Study Section
Biobehavioral and Behavioral Sciences Subcommittee (CHHD)
Program Officer
Ilekis, John V
Project Start
2019-01-01
Project End
2020-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617