Developmental programming: influence of sex steroids and mechanisms
发育规划:性类固醇的影响和机制
基本信息
- 批准号:8056426
- 负责人:
- 金额:$ 38.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-12-01 至 2014-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAngiotensinsAntiandrogen TherapyBlood PressureBlood VesselsCardiovascular PhysiologyCell physiologyChymosinDataDevelopmentDiseaseEndocrineEndothelial CellsEnvironmentEnvironmental Risk FactorEpidemiologyEstradiolExposure toFemaleFetal DevelopmentFlutamideFunctional disorderGenderGoalsGonadal Steroid HormonesGrowthHealthHormonesHumanHypertensionMesenteric ArteriesModelingMuscle functionObesityOrchiectomyOrganismOvariectomyPerinatal ExposurePlasmaPopulationPredispositionPrevention strategyProteinsRegulationRegulatory PathwayRenin-Angiotensin SystemReportingRiskRoleSeveritiesSexual DevelopmentSmooth MuscleSmooth Muscle MyocytesSteroid ReceptorsSteroidsSystemTestosteroneVariantVascular EndotheliumVascular Smooth Muscleage relatedcritical periodfetal programminghypertension treatmentin uteroinsightmaleoffspringpressurepreventprogramssexsteroid hormonesteroid hormone receptor
项目摘要
DESCRIPTION (provided by applicant): Adverse intrauterine environment during the critical period of fetal development predisposes organisms to increased risk for developing hypertension. We and others using a low-protein (LP) model of fetal programming demonstrated that hypertension in offspring is gender related, with a greater effect in males than females, and endocrine changes may underlie the development of hypertension. The central hypothesis is that sex steroid hormones, testosterone (T) and estradiol (E2), via interaction with a variety of regulatory path- ways, regulate the development and progression of maternal LP-induced hypertension in the offspring. Effects include changes in vascular steroid receptors, endothelial and smooth muscle (VSM) function, and vascular rennin angiotensin system (RAS). Three specific aims are proposed. Specific Aim 1: Investigate the influence of sex steroids on maternal LP-induced developmental origins of hypertension in male and female offspring. Specific Aim 1a. Is the onset and severity of hypertension related to changes in sex steroids? We hypothesize that endocrine dysfunction will precede the development of hypertension with a more pronounced effect in males than females. Specific Aim 1b. Are alterations in blood pressure (BP) in the offspring specific to changes in the levels of sex steroids? We hypothesize that OVX in females exacerbates, while OCX in males dampens, the onset and severity of hypertension, and these changes are reversed by respective steroid replacement and flutamide. Growth rate, adiposity, and changes in MAP and plasma T and E2 will be assessed. Specific Aim 2: Characterization of endothelial and VSM cell functions and their regulation by sex steroids in hypertensive offspring. We hypothesize that endocrine dysfunction will alter expression of steroid receptors, endothelial, and VSM functions in LP offspring, and these effects are hormone specific. Specific Aim 2a. Are alterations in BP in the offspring specific to changes in the levels of sex steroid receptors? Specific Aim 2b. Is endothelial cell function altered and related to changes in T and E2 levels in hypertensive offspring? Specific Aim 2c. Is VSM cell function altered and related to changes in T and E2 levels in hypertensive offspring? Specific Aim 2d. Are alterations in the function of endothelium and VSM specific to changes in T and E2 levels in hypertensive offspring? Specific Aim 3: Characterization of vascular RAS function and regulation by sex steroids in hypertensive offspring. We hypothesize that alteration in T and E2 levels will alter expression and activity of RAS components, and thus BP, in LP offspring. Specific Aim 3a. Is the function and expression of RAS components altered with age and related to changes in T and E2 levels in the hypertensive offspring? Specific Aim 3b. Are the expression and activity of RAS components in hyper- tensive offspring specific to changes in T and E2 using gonadectomy in LP offspring? The study will assess if these changes are reversed with respective hormones and flutamide. Collectively, these studies will yield important insights that could aid in developing sex-specific strategies for preventing and treating hypertension.
PUBLIC HEALTH RELEVANCE: Programming of adult health and disease appears to be dependent upon fetal exposure to various in utero environmental factors. Many models of fetal programming and epidemiological data in humans suggest gender-dependent variation in the susceptibility to hypertension. This proposal will yield important insights that could aid in the development of sex-specific strategies for the prevention and treatment of hypertension.
描述(由申请人提供):胎儿发育的关键时期不良内环境使生物体增加了出现高血压的风险。我们和其他人使用胎儿编程的低蛋白(LP)模型表明,后代的高血压与性别相关,对男性的影响比女性更大,而内分泌变化可能是高血压发展的基础。中心假设是性类固醇激素(睾丸激素(T)和雌二醇(E2))通过与多种调节路径的相互作用来调节母体LP诱导的后代高血压的发育和进展。影响包括血管类固醇受体的变化,内皮和平滑肌(VSM)功能以及血管肾上腺素血管紧张素系统(RAS)的变化。提出了三个具体目标。特定目的1:研究性类固醇对雄性LP诱导的男性和女性后代高血压发育起源的影响。特定目标1a。高血压的发作和严重程度与性类固醇变化有关吗?我们假设内分泌功能障碍将在高血压的发展之前,对男性的影响比女性更明显。 特定目标1B。性类固醇水平变化的后代中血压(BP)的变化是否会发生变化?我们假设女性中的OVX加剧了,而男性的OCX却降低了高血压的发作和严重程度,这些变化被各自的类固醇替代和氟他胺逆转。将评估生长速率,肥胖以及等离子T和E2的变化。特定目的2:内皮和VSM细胞功能的表征及其在高血压后代中对性类固醇的调节。我们假设内分泌功能障碍会改变LP后代中类固醇受体,内皮和VSM功能的表达,并且这些作用是激素特异性的。 特定目标2a。 BP的变化是性类固醇受体水平变化所特有的吗? 特定目标2B。内皮细胞功能是否改变并且与高血压后代T和E2水平的变化有关? 特定目标2C。 VSM细胞功能是否改变了高血压后代T和E2水平的变化?特定目标2D。高血压后代T和E2水平变化的内皮功能和VSM功能的变化是否会发生变化?特定目的3:在高血压后代中性类固醇调节血管RAS功能和调节的表征。我们假设T和E2水平的改变会改变RAS成分的表达和活性,从而改变LP后代的BP。 特定目标3A。 RAS成分的功能和表达是否随着年龄的增长而改变,并且与高血压后代T和E2水平的变化有关? 特定目标3B。在LP后代中使用Gonadadecto术在T和E2变化的过度后代中,RAS成分的表达和活性是否?该研究将评估这些变化是否用各自的激素和氟氨酰胺逆转。总的来说,这些研究将产生重要的见解,这些见解可以帮助制定针对性的预防和治疗高血压的策略。
公共卫生相关性:成人健康和疾病的编程似乎取决于胎儿暴露于子宫环境因素中的各种。人类中胎儿编程和流行病学数据的许多模型都表明性别依赖性差异在高血压易感性方面。该提案将产生重要的见解,可以帮助制定预防和治疗高血压的性别特定策略。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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CHANDRASEKHAR YALLAMPALLI其他文献
CHANDRASEKHAR YALLAMPALLI的其他文献
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{{ truncateString('CHANDRASEKHAR YALLAMPALLI', 18)}}的其他基金
Developmental programming: influence of sex steroids and mechanisms
发育规划:性类固醇的影响和机制
- 批准号:
8751210 - 财政年份:2010
- 资助金额:
$ 38.25万 - 项目类别:
Developmental programming: influence of sex steroids and mechanisms
发育规划:性类固醇的影响和机制
- 批准号:
8383460 - 财政年份:2010
- 资助金额:
$ 38.25万 - 项目类别:
Developmental programming: influence of sex steroids and mechanisms
发育规划:性类固醇的影响和机制
- 批准号:
8197579 - 财政年份:2010
- 资助金额:
$ 38.25万 - 项目类别:
Nitric oxide regulation of CD55 and infection
一氧化氮对 CD55 和感染的调节
- 批准号:
8206846 - 财政年份:2009
- 资助金额:
$ 38.25万 - 项目类别:
Nitric oxide regulation of CD55 and infection
一氧化氮对 CD55 和感染的调节
- 批准号:
8403523 - 财政年份:2009
- 资助金额:
$ 38.25万 - 项目类别:
Nitric oxide regulation of CD55 and infection
一氧化氮对 CD55 和感染的调节
- 批准号:
8794626 - 财政年份:2009
- 资助金额:
$ 38.25万 - 项目类别:
Nitric oxide regulation of CD55 and infection
一氧化氮对 CD55 和感染的调节
- 批准号:
8004069 - 财政年份:2009
- 资助金额:
$ 38.25万 - 项目类别:
Nitric oxide regulation of CD55 and infection
一氧化氮对 CD55 和感染的调节
- 批准号:
7759623 - 财政年份:2009
- 资助金额:
$ 38.25万 - 项目类别:
Low birth weight, uterine infection, and nitric oxide
低出生体重、子宫感染和一氧化氮
- 批准号:
6695283 - 财政年份:2002
- 资助金额:
$ 38.25万 - 项目类别:
Low birth weight, uterine infection, and nitric oxide
低出生体重、子宫感染和一氧化氮
- 批准号:
7151219 - 财政年份:2002
- 资助金额:
$ 38.25万 - 项目类别:
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