Hypertension in Adult IUGR Offspring: Beneficial Effects of Perinatal Intervention
Hypertension in Adult IUGR Offspring: Beneficial Effects of Perinatal Intervention
批准号:
10064105
负责人:
Barbara T Alexander
金额:
$45.94万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-12-01 至 2022-11-30
关键词:
AdultAgeAgingAmino AcidsAngiotensin IIAntioxidantsAttenuatedAutoantibodiesAutoimmune DiseasesBirthBlood CirculationBlood PressureCardiovascular DiseasesCardiovascular systemCarrier ProteinsCell AgingChronicChronic DiseaseDataDevelopmentDrug Delivery SystemsElastinEndothelinEtiologyEventExposure toFemaleFetal GrowthFetal Growth RetardationFetal WeightFetusGrowthHealth BenefitHumanHypersensitivityHypertensionIndividualInflammationInflammatoryInterventionIschemiaKidneyLaboratoriesLifeLow Birth Weight InfantMaternal HealthMediatingMediator of activation proteinMicroRNAsMitochondriaModelingMothersNutrientOxidation-ReductionOxidative StressPathogenesisPathway interactionsPeptidesPerfusionPharmacotherapyPhenotypePre-EclampsiaPregnancyPremature BirthPremature aging syndromeRattusReactive Oxygen SpeciesReceptor, Angiotensin, Type 1ReportingRiskRisk FactorsRoleSourceStabilizing AgentsStressTNF geneTeratogenic effectsTestingTherapeuticTherapeutic AgentsTherapeutic InterventionUterusWeightWestern WorldWomanantioxidant enzymecardiovascular risk factorclinically relevantcytokineemerging adultenzyme activityfetalimprovedmalemiddle agemitochondrial dysfunctionnormotensivenoveloffspringperinatal interventionpolypeptidepregnantprenatal exposurepressurepreventprogramsprotein expressionpupreceptorsenescencesextempoltherapeutic targetvectoryoung adult
中文摘要
大量研究表明,母亲患有先兆子痫的人血压(BP)会升高
(PE)。目前,PE的唯一治疗选择是早产。然而,在37周前出生导致
早产或低出生体重(LBW)也与后代血压升高有关。因此,有一个关键的
需要为PE开发治疗干预措施,不仅改善产妇健康,还能减轻胎儿
生长受限,子代血压升高。特征明确的子宫缩小模型
妊娠大鼠的灌流压(RUPP)模拟了PE的许多方面。亚历山大实验室报告说
LBW或宫内发育受限(IUGR)子代早期男性血压升高而女性血压无明显变化
成人期。男性IUGR患者血压升高的原因与血压对血管紧张素II(Ang)的敏感性增加有关
Ii)和增加肾脏的氧化应激;而女性IUGR的肾脏抗氧化酶活性升高
在年轻的成年期血压正常。初步数据显示,男性IUGR患者AT1-AA水平升高
提示可能是血管紧张素Ⅱ敏感性增强的介质,但肾脏氧化增加的病因
压力还不清楚。发育损害模型中肾脏线粒体应激的作用也是
未知,但可能涉及microRNA。因此,该项目将使用临床相关的IUGR模型来测试
产妇干预改善胎盘血流和营养物质转运缓解胎盘病变的新假说
胎儿发育受损,导致IUGR后代免受心血管疾病的保护。此外,我们还将测试
增加AT1-AA和microRNA介导的线粒体氧化应激的新假说具有性别特异性
在IUGR子代血压升高的病因中。目标1将检验这一假设,即母亲的治疗
干预改善子宫胎盘的血流灌注和营养物质的转移,减轻IUGR和发育
血压升高的起源限制了后代的生长。目标2:将检验增加的假设
AT1-AA导致男性发育受限后代的血压因性别而升高,而且
母体治疗干预通过降低AT1-AA来缓解男性IUGR患者血压的升高
活性和对血管紧张素II的敏感性增强。目标3将检验肾脏氧化增加的假设
雄性生长受限后代的应激源于性别特异性引起的线粒体功能障碍
氧化还原相关microRNAs在青春期的表达变化及其与早衰的关系
雌性发育受限后代的心血管风险增加。
英文摘要
Numerous studies indicate blood pressure (BP) is increased in individuals whose mothers had preeclampsia
(PE). Currently the only treatment option for PE involves early delivery. Yet, birth before 37 weeks resulting in
preterm or low birth weight (LBW) is also associated with increased BP in the offspring. Thus, there is a critical
need to develop therapeutic interventions for PE that not only improve maternal health but also mitigate fetal
growth restriction and increased BP in the offspring. The well-characterized model of Reduced Uterine
Perfusion Pressure (RUPP) in the pregnant rat mimics many facets of PE. The Alexander laboratory reports
that BP is increased in male but not female LBW or intrauterine growth restricted (IUGR) offspring in early
adulthood. The etiology of increased BP in male IUGR involves enhanced BP sensitivity to angiotensin II (ANG
II) and increased renal oxidative stress; whereas, renal anti-oxidant enzyme activity elevated in female IUGR
that are normotensive in young adulthood. Preliminary data indicate AT1-AA is elevated in male IUGR
suggesting a potential mediator of enhanced ANG II sensitivity, but the etiology of increased renal oxidative
stress is not yet clear. The role of mitochondrial stress in the kidney in models of developmental insult is also
unknown but may involve microRNAs. Thus, this project will use a clinically relevant model of IUGR to test the
novel hypothesis that maternal interventions improve placental perfusion and transfer of nutrients alleviating
impaired fetal growth resulting in protection from CV disease in IUGR offspring. Furthermore, we will test the
novel hypotheses that elevated AT1-AA and microRNA-mediated mitochondrial oxidative stress is sex-specific
in the etiology of increased BP in IUGR offspring. Aim 1 will test the hypothesis that maternal therapeutic
interventions improve uteroplacental perfusion and transfer of nutrients mitigating IUGR and the developmental
origins of increased blood pressure in growth restricted offspring. Aim 2: will test the hypothesis that increased
AT1-AA contributes to the sex-specific increase in blood pressure in male growth restricted offspring, and that
maternal therapeutic interventions mitigate this increase in blood pressure in male IUGR by reducing AT1-AA
activity and enhanced sensitivity to angiotensin II. Aim 3 will test the hypothesis that increased renal oxidative
stress in male growth restricted offspring originates from mitochondrial dysfunction induced by sex-specific
altered expression of redox-related microRNAs in young adulthood and that premature aging contributes to
increased CV risk in female growth restricted offspring.
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Bioanalytical, Cardiometabolic Phenotyping, Imaging and Histology Core
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批准号:10630579
-
项目类别:
-
资助金额:$26.43万
-
财政年份:2023
-
负责人:Barbara T Alexander
-
依托单位:
Hypertension in Adult IUGR Offspring: Beneficial Effects of Perinatal Intervention
-
批准号:9903661
-
项目类别:
-
资助金额:$45.94万
-
财政年份:2019
-
负责人:Barbara T Alexander
-
依托单位:
Hypertension in Adult IUGR Offspring: Beneficial Effects of Perinatal Intervention
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批准号:10326824
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项目类别:
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Core B - Bioanalytical, Mass Spectroscopy, Imaging and Histology Core
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Low birth weight, the kidney, and hypertension
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负责人:Barbara T Alexander
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依托单位:
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资助金额:$33.3万
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资助金额:$33.3万
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批准号:8464768
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批准号:6929865
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