Placental Mitochondrial Function in Gestational Diabetes
Placental Mitochondrial Function in Gestational Diabetes
批准号:
9920017
负责人:
LESLIE MYATT
金额:
$53.66万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-09-12 至 2023-05-31
关键词:
AddressAdverse eventAffectAntioxidantsApoptosisCell CycleComplexCongenital AbnormalityDataDependenceDevelopmentDiabetes MellitusDichloroacetateDrug TargetingElderlyEnzymesEventFatty AcidsFeedbackFemaleFetal GrowthFetal Growth RetardationFetusFrequenciesFunctional disorderFutureGenerationsGestational AgeGestational DiabetesGlucoseGlutamineGlycolysisGoalsGrowth and Development functionHyperlipidemiaIn VitroInfantLipidsMaintenanceMelatoninMembrane PotentialsMetabolicMetabolismMitochondriaMothersNewborn InfantNon-Insulin-Dependent Diabetes MellitusObesityOxidative PhosphorylationOxidative StressPathway interactionsPharmaceutical PreparationsPharmacologyPlacentaPlasmaPre-EclampsiaPredispositionPregnancyPregnancy OutcomePregnancy in DiabeticsPrevalenceRespirationSignal TransductionSteroidsSubstrate SpecificitySuperoxidesTestingTherapeuticThinnessTissuesWomanWomen&aposs GroupWorkadverse outcomeantioxidant enzymecell growth regulationfatty acid oxidationfetalfetal programmingflexibilitygeneration differenceimprovedimproved outcomeinnovationmalematernal hyperglycemiamaternal obesitymetabolomemetabolomicsmitochondrial dysfunctionnovelobesity developmentoffspringoxidationprepregnancypreventprogramssexual dimorphismstillbirthtrophoblastuptake
中文摘要
项目摘要
肥胖(BMI>30)和妊娠期糖尿病(GDM)的发生频率都在增加,
妊娠期不良事件,包括死胎、晚年发生2型糖尿病,
它们还为胎儿随后的肥胖症和糖尿病的发展编程。目前,这些不良
结果可以减少,但不能通过治疗GDM妇女预防。随着胎盘调节
母体代谢、胎儿生长和发育,其功能的改变影响母体和胎儿。
支持胎盘功能的能量通过糖酵解、β-氧化和氧化磷酸化产生
使用葡萄糖和脂肪酸作为底物。母体高血糖和高脂血症伴肥胖,
GDM改变胎盘可用底物的类型/量,因此可能改变胎盘代谢
和能源生产。最近,我们发现脂肪酸转运蛋白和相关酶的表达与
肥胖孕妇胎盘中脂肪酸的β-氧化发生改变,
方式我们还证明了线粒体呼吸、线粒体复合物的表达和
妊娠合并肥胖的妇女滋养层中ATP的生成减少,
与瘦对照组相比,妊娠合并A2型GDM(需要药物治疗)也是如此。这是
与增加的氧化应激、代谢能力(糖酵解时不能使用其他底物)
在肥胖症中,糖酵解增加。我们有令人兴奋的初步数据,
胎盘也可以利用谷氨酰胺产生能量,
脂肪酸和谷氨酰胺随肥胖和GDM而改变。线粒体参与许多胎盘
功能,产生超氧阴离子。在许多病理生理状态下,包括胎盘肥胖和
GDM有过量的超氧化物生成导致氧化应激,从而产生反馈性损伤
因此,有针对性的药理学方法,以改善线粒体
功能得到广泛推广。最近,我们证明了氧化应激和
肥胖妇女胎盘中的抗氧化酶,再次以性别二型的方式,
抗氧化剂褪黑激素或代谢调节剂二氯乙酸(DCA)将改善线粒体
肥胖妇女滋养层的呼吸。使用来自8名孕妇和胎儿的血浆和胎盘组织,
妇女组(孕前瘦或肥胖,有或无GDM,胎儿为男性或女性(n=8
每组),我们将检验以下假设:
胎盘肥胖GDM连同改变脂肪酸摄取和氧化导致减少
氧化磷酸化和改变的燃料灵活性的线粒体支持胎盘功能,可以
通过新的特异性线粒体靶向来改善/正常化,以减少氧化应激或重定向细胞
新陈代谢.这种转化工作可能成为肥胖或GDM未来治疗方法的基础。
英文摘要
Project Summary
Obesity (BMI>30) and gestational diabetes (GDM), which are both increasing in frequency, cause more
adverse events in pregnancy, including stillbirth, development of type 2 diabetes in later life and importantly
they also program the fetus for subsequent development of obesity and diabetes. Currently these adverse
outcomes can be reduced but not prevented by treating women with GDM. As the placenta regulates
maternal metabolism, fetal growth and development, alterations in its function affects both mother and fetus.
Energy to support placental function is generated via glycolysis, β-oxidation and oxidative phosphorylation
using glucose and fatty acids as substrates. Maternal hyperglycemia and hyperlipidemia seen with obesity and
GDM alter the type/amount of substrates available to the placenta and hence may alter placental metabolism
and energy generation. Recently we found that expression of fatty acid transporters and enzymes involved in
β-oxidation of fatty acids was altered in the placenta of pregnancies with obesity in a sexually dimorphic
manner. We also demonstrated that mitochondrial respiration, expression of mitochondrial complexes and
generation of ATP are reduced in trophoblast from women with pregnancies complicated by obesity and more
so in pregnancies complicated by type A2 GDM (requiring medication) compared to lean controls. This is
associated with increased oxidative stress, metabolic inflexibility (cannot use other substrates when glycolysis
is inhibited) in obesity, and increased glycolysis with GDM. We have exciting preliminary data that the
placenta can also use glutamine for energy generation and that placental fuel dependency between glucose,
fatty acids and glutamine is altered with obesity and GDM. Mitochondria which are involved in many placental
functions, generate superoxide anion. In many pathophysiologic states, including the placenta with obesity and
GDM there is excessive superoxide generation leading to oxidative stress, which can feedback and damage
mitochondria in a vicious cycle hence targeted pharmacologic approaches to improve mitochondrial
function are being widely promoted. Recently we demonstrated differences in oxidative stress and in
antioxidant enzymes in the placenta of obese women, again in a sexually dimorphic manner and have shown
that the antioxidant melatonin or the metabolic modulator dichloroacetate (DCA) will improve mitochondrial
respiration in trophoblast from obese women. Using maternal and fetal plasma and placental tissue from 8
groups of women (prepregnancy lean or obese, with or without GDM with either a male or a female fetus (n=8
each group) we will test the hypothesis that altered metabolomic and lipid profiles and oxidative stress seen in
the placenta with obesity GDM together with altered fatty acid uptake and oxidation leads to decreased
oxidative phosphorylation and altered fuel flexibility of mitochondria supporting placental function which can be
improved/normalized by novel specific mitochondrial targeting to reduce oxidative stress or to redirect cellular
metabolism. This translational work may form the basis for future therapeutic approaches in obesity or GDM.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
A dynamical model of preeclampsia development
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批准号:9978462
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项目类别:
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资助金额:$24.15万
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财政年份:2020
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负责人:LESLIE MYATT
-
依托单位:
Placental Mitochondrial Function in Gestational Diabetes
-
批准号:10396015
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项目类别:
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资助金额:$33.41万
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财政年份:2018
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负责人:LESLIE MYATT
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依托单位:
Effects of a Maternal Obesogenic Environment on DNA Methylation in the Placenta
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批准号:8707875
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项目类别:
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资助金额:$13.76万
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财政年份:2013
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负责人:LESLIE MYATT
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依托单位:
Role of miR-210 in placental mitochondrial metabolism
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批准号:9353444
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项目类别:
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资助金额:$29.58万
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财政年份:2013
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负责人:LESLIE MYATT
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依托单位:
Role of miR-210 in placental mitochondrial metabolism
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批准号:8741981
-
项目类别:
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资助金额:$30.15万
-
财政年份:2013
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负责人:LESLIE MYATT
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依托单位:
Role of miR-210 in placental mitochondrial metabolism
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批准号:8650502
-
项目类别:
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资助金额:$31.02万
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财政年份:2013
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负责人:LESLIE MYATT
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依托单位:
Role of miR-210 in placental mitochondrial metabolism
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批准号:8895208
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项目类别:
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资助金额:$6.01万
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财政年份:2013
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负责人:LESLIE MYATT
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依托单位:
Effects of a Maternal Obesogenic Environment on DNA Methylation in the Placenta
-
批准号:9276325
-
项目类别:
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资助金额:$4.4万
-
财政年份:2013
-
负责人:LESLIE MYATT
-
依托单位:
Effects of a Maternal Obesogenic Environment on DNA Methylation in the Placenta
-
批准号:8491926
-
项目类别:
-
资助金额:$22.43万
-
财政年份:2013
-
负责人:LESLIE MYATT
-
依托单位:
Molecular Mechanisms Linking Placental Nutrient Sensing and Fetal Programming
-
批准号:8432440
-
项目类别:
-
资助金额:$16.21万
-
财政年份:2012
-
负责人:LESLIE MYATT
-
依托单位:
Aspen Perinatal Biology Symposium
-
批准号:7224640
-
项目类别:
-
资助金额:$1.0万
-
财政年份:2007
-
负责人:LESLIE MYATT
-
依托单位:
International Federation of Placenta Association Meeting
-
批准号:7271143
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项目类别:
-
资助金额:$1.0万
-
财政年份:2005
-
负责人:LESLIE MYATT
-
依托单位:
International Federation of Placenta Association Meeting
-
批准号:7097491
-
项目类别:
-
资助金额:$1.0万
-
财政年份:2005
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负责人:LESLIE MYATT
-
依托单位:
International Federation of Placenta Association Meeting
-
批准号:8701180
-
项目类别:
-
资助金额:$1.0万
-
财政年份:2005
-
负责人:LESLIE MYATT
-
依托单位:
International Federation of Placenta Association Meeting
-
批准号:7663245
-
项目类别:
-
资助金额:$1.0万
-
财政年份:2005
-
负责人:LESLIE MYATT
-
依托单位:
International Federation of Placenta Association Meeting
-
批准号:8066420
-
项目类别:
-
资助金额:$1.0万
-
财政年份:2005
-
负责人:LESLIE MYATT
-
依托单位:
International Federation of Placenta Association Meeting
-
批准号:8304159
-
项目类别:
-
资助金额:$1.0万
-
财政年份:2005
-
负责人:LESLIE MYATT
-
依托单位:
International Federation of Placenta Association Meeting
-
批准号:8514659
-
项目类别:
-
资助金额:$1.0万
-
财政年份:2005
-
负责人:LESLIE MYATT
-
依托单位:
Cincinnati Interdisciplinary Women's Health Research Career Training Grant
-
批准号:7118726
-
项目类别:
-
资助金额:$49.84万
-
财政年份:2005
-
负责人:LESLIE MYATT
-
依托单位:
International Federation of Placenta Association Meeting
-
批准号:7001920
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项目类别:
-
资助金额:$1.0万
-
财政年份:2005
-
负责人:LESLIE MYATT
-
依托单位:
海外基金