A Novel Mechanistic Framework for FASD Etiology.

FASD 病因学的新机制框架。

基本信息

  • 批准号:
    10377467
  • 负责人:
  • 金额:
    $ 37.96万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-04-15 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

Fetal Alcohol Spectrum Disorders (FASD) affects an estimated 2–5% of young school age children in the U.S., with an estimated cost of $1.4 million per individual. Two cardinal outcomes of FASD are fetal growth restriction and neurodevelopmental deficits. Efforts to successfully prevent or ameliorate these teratogenic effects of alcohol abuse have been impeded by a limited understanding of alcohol’s complex mechanisms of action, which impact multiple organ systems. In addition, etiological reports on FASD outcomes have been mostly limited to investigating indirect downstream mediators. We propose the molecular pathway governing phosphatidylethanol (PEth; 100% specific, most sensitive biomarker for gestational alcohol exposure) formation can yield novel insights into FASD etiology, as during alcohol metabolism, phosphatidylcholine is hydrolyzed to PEth instead of phosphatidic acid (PA, an essential nutrient for growth/neuron development). In an established FASD model, our novel preliminary data shows alcohol decreases PA bioavailability and concurrently increases PEth levels in maternal and fetal compartments. Our data also show alcohol-induced impairment of maternal uterine artery (related to fetal growth) and fetal brain vascular (related to neurodevelopmental outcomes) adaptations. Interestingly, PA addition in vitro to the uterine and middle cerebral arteries reverses alcohol-induced dysfunction in these vessels, and in vivo PA administration reverses FASD growth deficit. Our data also identify a role for endothelial nitric oxide (NO) synthase (eNOS) and mTORC1 signaling in this alcohol/PEth/PA framework. In Aim #1, we hypothesize that in our FASD model, PA plays a major role in alcohol-mediated vasodilatory deficits and the related eNOS pathway in maternal uterine and developing cranially directed arteries, and that alcohol impairs the NO system via PA-mediated mTORC1 system alteration. Following mechanistic in vitro blockade of PA, mTORC1, and related signaling, we will assess uterine and developing cranially directed arterial adaptations using arteriography, LC-MS/MS, immunoblotting, immunofluorescence, RNA-seq, RT-PCR, and patch clamp. In Aim#2, we hypothesize PA administration in vivo reverses alcohol-induced decreases in uterine artery and fetal cranially directed blood flow, and improves fetal nutrient delivery, growth phenotypes, and deficits in alcohol-sensitive neurobiological outcomes. We will measure growth indices, uterine blood flow, uterine O2/nutrient delivery, fetal cranially directed blood flow, and neuronal function/morphology to assess the role of PA in the etiology of two cardinal FASD outcomes. We anticipate that the proposed experiments will provide a much-needed breakthrough in the FASD field by identifying a promising etiological molecular pathway(s) for FASD growth and/or neurodevelopmental deficits. These studies will pave way for future novel prevention/treatment studies strategically aimed at rescuing FASD cardinal outcome phenotypes through manipulation of direct alcohol targets.
胎儿酒精谱系障碍(FASD)影响美国估计2-5%的学龄儿童,估计每人费用为140万美元。FASD的两个主要结局是胎儿生长受限和神经发育缺陷。成功地预防或改善酒精滥用的致畸作用的努力受到了对酒精影响多器官系统的复杂作用机制的有限理解的阻碍。此外,关于FASD结局的病因学报告大多局限于调查间接下游介质。 我们提出控制磷脂酰乙醇(PEth; 100%特异性,妊娠期酒精暴露最敏感的生物标志物)形成的分子途径可以产生对FASD病因学的新见解, 在酒精代谢过程中,磷脂酰胆碱被水解成PEth而不是磷脂酸(PA,生长/神经元发育的必需营养素)。在建立的FASD模型中,我们的新的初步数据显示,酒精降低PA生物利用度,同时增加母亲和胎儿室中的PEth水平。我们的数据还显示了酒精诱导的母体子宫动脉(与胎儿生长有关)和胎儿脑血管(与神经发育结果有关)适应性损害。有趣的是,PA在体外子宫动脉和大脑中动脉逆转酒精诱导的功能障碍,在这些血管,在体内PA管理逆转FASD的生长缺陷。我们的数据还确定了内皮型一氧化氮(NO)合酶(eNOS)和mTORC 1信号在这个酒精/PEth/PA框架的作用。在目标#1中,我们假设在我们的FASD模型中,PA在母体子宫和发育中的颅向动脉中的酒精介导的血管舒张缺陷和相关eNOS通路中起主要作用,并且酒精通过PA介导的mTORC 1系统改变损害NO系统。在体外机械阻断PA、mTORC 1和相关信号传导后,我们将评估子宫和发育中的颅向 使用动脉造影术、LC-MS/MS、免疫印迹、免疫荧光、RNA-seq、RT-PCR和膜片钳进行动脉适应。在目标#2中,我们假设PA体内给药逆转了酒精诱导的子宫动脉和胎儿颅侧血流减少,并改善了胎儿营养输送、生长表型和酒精敏感性神经生物学结局缺陷。我们将测量生长指数、子宫血流量、子宫O2/营养输送、胎儿颅侧定向血流量和神经元功能/形态,以评估PA在两种主要FASD结局病因中的作用。 我们预计,所提出的实验将通过鉴定FASD生长和/或神经发育的有希望的病因学分子途径,在FASD领域提供急需的突破。 赤字这些研究将为未来新的预防/治疗研究铺平道路,这些研究的战略目标是通过操纵直接的酒精靶点来挽救FASD的主要结局表型。

项目成果

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Jayanth Ramadoss其他文献

Jayanth Ramadoss的其他文献

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{{ truncateString('Jayanth Ramadoss', 18)}}的其他基金

ELECTRONIC CIGARETTE VAPING & VASCULAR SEQUELAE IN THE UTERUS DURING PREGNANCY.
电子烟
  • 批准号:
    10540752
  • 财政年份:
    2021
  • 资助金额:
    $ 37.96万
  • 项目类别:
ELECTRONIC CIGARETTE VAPING & VASCULAR SEQUELAE IN THE UTERUS DURING PREGNANCY.
电子烟
  • 批准号:
    10459954
  • 财政年份:
    2021
  • 资助金额:
    $ 37.96万
  • 项目类别:
ELECTRONIC CIGARETTE VAPING & VASCULAR SEQUELAE IN THE UTERUS DURING PREGNANCY.
电子烟
  • 批准号:
    10324577
  • 财政年份:
    2021
  • 资助金额:
    $ 37.96万
  • 项目类别:
ELECTRONIC CIGARETTE VAPING & VASCULAR SEQUELAE IN THE UTERUS DURING PREGNANCY
电子烟
  • 批准号:
    10116886
  • 财政年份:
    2021
  • 资助金额:
    $ 37.96万
  • 项目类别:
A Novel Platform for Maternal Alcohol Consumption Screening
孕产妇酒精摄入量筛查的新平台
  • 批准号:
    8822061
  • 财政年份:
    2015
  • 资助金额:
    $ 37.96万
  • 项目类别:
A Novel Mechanistic Framework for FASD Etiology.
FASD 病因学的新机制框架。
  • 批准号:
    10598031
  • 财政年份:
    2015
  • 资助金额:
    $ 37.96万
  • 项目类别:
Alcohol and Maternal Uterine Vascular Adaptations in Pregnancy
妊娠期酒精与母体子宫血管适应
  • 批准号:
    9053392
  • 财政年份:
    2015
  • 资助金额:
    $ 37.96万
  • 项目类别:
A Novel Mechanistic Framework for FASD Etiology.
FASD 病因学的新机制框架。
  • 批准号:
    10459965
  • 财政年份:
    2015
  • 资助金额:
    $ 37.96万
  • 项目类别:
A Novel Platform for Maternal Alcohol Consumption Screening
孕产妇酒精摄入量筛查的新平台
  • 批准号:
    9136036
  • 财政年份:
    2015
  • 资助金额:
    $ 37.96万
  • 项目类别:
Maternal Uterine Vascular Origins of Fetal Alcohol Spectrum Disorders
胎儿酒精谱系疾病的母体子宫血管起源
  • 批准号:
    8040970
  • 财政年份:
    2010
  • 资助金额:
    $ 37.96万
  • 项目类别:

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