Antenatal Dietary Supplementation is a Risk Factor for Infant Atopy Through Epige

Epige 发现产前膳食补充剂是婴儿特应性的危险因素

基本信息

  • 批准号:
    7821778
  • 负责人:
  • 金额:
    $ 49.99万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-09-30 至 2011-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Antenatal Dietary Supplementation is a Risk Factor for Infant Atopy Through Epigenetics This application addresses broad Challenge Area (03): Biomarker Discovery and Validation, topic 03-HL-101: Identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction. The challenge addressed in this proposal is to understand the "epidemic" increase in the prevalence of atopic diseases and the extent to which epigenetic mechanisms contribute to the etiology and prevalence of these diseases in infants and young children. Recent data in mice suggest that in utero dietary factors can modify the heritable risk of allergic airway disease during a vulnerable period of fetal development through epigenetic regulation in the form of enhanced DNA methylation. Remarkably, the increase in atopic diseases appears to correlate with the institution of widespread antenatal supplementation with folate, a methyl donor. We hypothesize that maternal CpG methylation patterns that affect expression of atopy-related genes are different in expectant mothers of infants at high risk as compared to expectant mothers of infants at low risk of atopy, and that antenatal dietary supplementation with methyl donors such as folate, vitamin B12, and choline enhance these epigenetic differences in infants with atopy. Transmission of CpG methylation patterns from high risk mothers to their infants will be associated with an increased risk of atopy in their offspring. Combining molecular genetics tools, we will determine if antenatal supplementation with methyl donors adversely affects pregnant mothers and their immediate offspring, increasing the risk for atopy through modification of protective genes. To identify genes that are differently methylated in expectant mothers at high and low risk of atopic infants, based on the parental history of atopy, global DNA methylation assays will be performed on maternal PBMC collected at the time of delivery using the recently developed Comprehensive High-throughput Arrays for Relative Methylation (CHARM) method. We predict that DNA methylation patterns at specific CpG dinucleotide sites will track with mothers at high risk of atopy. To assess in utero transmission patterns, global DNA methylation assays will also be performed in cord blood of infants at high risk of atopy, and their methylation patterns will be compared with those of their mothers. We predict in utero transmission of enhanced maternal DNA methylation patterns from mothers of infants at high risk of atopy to their fetuses resulting in an atopic phenotype of their children through transmission of epigenetically-modified expression of atopy-related genes. To study the effect of methyl donor concentrations in blood on CpG methylation, we will measure concentrations of folate, vitamin B12, and choline in blood of high risk mothers at delivery and cord blood of their infants, and correlate methyl donor concentrations with DNA methylation patterns and intensity. We predict that increased concentrations of methyl donors in the maternal blood through prenatal dietary supplementation, in particular folate, B12 and choline, will enhance maternal DNA methylation and its transmission to the fetus. In expectant mothers of an infant at high risk of atopy, methyl donor concentrations will correlate with an increased risk of their children having an atopic infant phenotype through epigenetic DNA modification. Clinical data on manifestations of atopic diseases during the first two years of life in children born to mothers participating in this study will be collected by questionnaires. We expect to identify and validate clinically relevant, quantifiable biomarkers of atopy, and in this project to identify more precisely the risks of antenatal supplementation with methyl donors in expectant mothers for having an atopic child and to identify those who are most likely to benefit from specific interventions for prevention or treatment. PUBLIC HEALTH RELEVANCE: There is widespread use of antenatal dietary supplementation with the goal of preventing in utero and neonatal abnormalities, but there has been little investigation about the potential risks of such interventions in expectant mothers. Folic acid, vitamin B12, and choline are methyl donors that, taken during pregnancy, have the potential through hypermethylation to alter the expression of genes that regulate development of allergy, increasing the risk in babies for developing an allergic disease. Our research team proposes to determine if such concerns about methyl donor supplementation are justified and pose a real threat in expectant mothers already at risk for transmitting an atopic genetic predisposition to their infants.
描述(由申请人提供):孕期膳食补充剂是通过表观遗传学导致婴儿特应性的风险因素。本申请涉及广泛的挑战领域(03):生物标志物发现和验证,主题03-HL-101:确定和验证血液、血管、心脏和呼吸道功能障碍诊断和治疗反应的临床相关、可量化的生物标志物。本提案所涉及的挑战是了解特应性疾病患病率的“流行性”增加以及表观遗传机制对婴幼儿这些疾病的病因学和患病率的影响程度。最近的小鼠数据表明,在子宫内的饮食因素可以修改过敏性气道疾病的遗传风险在胎儿发育的脆弱时期,通过表观遗传调节的形式增强DNA甲基化。值得注意的是,特应性疾病的增加似乎与广泛的产前补充叶酸(一种甲基供体)有关。我们假设,母亲的CpG甲基化模式,影响表达的特应性相关基因是不同的,在高风险的婴儿的孕妇相比,在低风险的婴儿的孕妇,产前膳食补充甲基供体,如叶酸,维生素B12,胆碱增强这些表观遗传差异的特应性婴儿。CpG甲基化模式从高风险母亲向其婴儿的传递将与其后代中特应性的风险增加相关。结合分子遗传学工具,我们将确定产前补充甲基供体是否会对孕妇及其直系后代产生不利影响,通过修改保护基因增加特应性的风险。为了鉴定特应性婴儿高风险和低风险的孕妇中甲基化不同的基因,基于特应性的父母病史,将使用最近开发的相对甲基化综合高通量阵列(CHARM)方法对分娩时收集的母体PBMC进行全局DNA甲基化测定。我们预测,DNA甲基化模式在特定的CpG二核苷酸位点将跟踪与母亲在高风险的特应性。为了评估宫内传播模式,还将在特应性高风险婴儿的脐带血中进行整体DNA甲基化测定,并将其甲基化模式与其母亲的甲基化模式进行比较。我们预测,在子宫内传输增强的母体DNA甲基化模式,从母亲的婴儿在高风险的特应性,以他们的胎儿,导致一个特应性表型的儿童通过传输表观遗传修饰的特应性相关基因的表达。为了研究血液中甲基供体浓度对CpG甲基化的影响,我们将测量分娩时高风险母亲血液和婴儿脐带血中叶酸、维生素B12和胆碱的浓度,并将甲基供体浓度与DNA甲基化模式和强度相关联。我们预测,通过产前膳食补充剂,特别是叶酸,B12和胆碱,增加母体血液中甲基供体的浓度,将增强母体DNA甲基化及其向胎儿的传递。对于患有特应性高风险婴儿的孕妇来说,甲基供体浓度将与其孩子通过表观遗传DNA修饰而具有特应性婴儿表型的风险增加相关。将通过问卷调查收集参与本研究的母亲所生儿童在出生后头两年期间特应性疾病表现的临床数据。我们期望识别和验证临床相关的,可量化的特应性生物标志物,并在本项目中,更精确地确定产前补充甲基供体的风险,孕妇有一个特应性儿童,并确定那些最有可能受益于特定的干预措施,预防或治疗。 公共卫生关系:人们广泛使用产前膳食补充剂,目的是预防子宫内和新生儿畸形,但几乎没有调查过这种干预措施对孕妇的潜在风险。叶酸,维生素B12和胆碱是甲基供体,在怀孕期间服用,有可能通过超甲基化改变调节过敏发展的基因表达,增加婴儿患过敏性疾病的风险。我们的研究小组建议确定这种对甲基供体补充剂的担忧是否合理,并对已经存在将特应性遗传易感性传递给婴儿风险的孕妇构成真实的威胁。

项目成果

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ERWIN William GELFAND其他文献

ERWIN William GELFAND的其他文献

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{{ truncateString('ERWIN William GELFAND', 18)}}的其他基金

LTB4-BLT1 Interactions in the Pathogenesis of Allergic Airway Disease
LTB4-BLT1 相互作用在过敏性气道疾病发病机制中的作用
  • 批准号:
    8147497
  • 财政年份:
    2010
  • 资助金额:
    $ 49.99万
  • 项目类别:
Administrative Core A
行政核心A
  • 批准号:
    8147505
  • 财政年份:
    2010
  • 资助金额:
    $ 49.99万
  • 项目类别:
Naturally Occurring T Regulatory Cells Control Airway Hyperresponsiveness
天然存在的 T 调节细胞控制气道高反应性
  • 批准号:
    7910663
  • 财政年份:
    2009
  • 资助金额:
    $ 49.99万
  • 项目类别:
Antenatal Dietary Supplementation is a Risk Factor for Infant Atopy Through Epige
Epige 发现产前膳食补充剂是婴儿特应性的危险因素
  • 批准号:
    7942064
  • 财政年份:
    2009
  • 资助金额:
    $ 49.99万
  • 项目类别:
Naturally Occurring T Regulatory Cells Control Airway Hyperresponsiveness
天然存在的 T 调节细胞控制气道高反应性
  • 批准号:
    7729164
  • 财政年份:
    2009
  • 资助金额:
    $ 49.99万
  • 项目类别:
Naturally Occurring T Regulatory Cells Control Airway Hyperresponsiveness
天然存在的 T 调节细胞控制气道高反应性
  • 批准号:
    8310977
  • 财政年份:
    2009
  • 资助金额:
    $ 49.99万
  • 项目类别:
Naturally Occurring T Regulatory Cells Control Airway Hyperresponsiveness
天然存在的 T 调节细胞控制气道高反应性
  • 批准号:
    8503580
  • 财政年份:
    2009
  • 资助金额:
    $ 49.99万
  • 项目类别:
Naturally Occurring T Regulatory Cells Control Airway Hyperresponsiveness
天然存在的 T 调节细胞控制气道高反应性
  • 批准号:
    8085839
  • 财政年份:
    2009
  • 资助金额:
    $ 49.99万
  • 项目类别:
Naturally occurring T regulatory cells control airway hyperresponsiveness
天然存在的 T 调节细胞控制气道高反应性
  • 批准号:
    7683378
  • 财政年份:
    2008
  • 资助金额:
    $ 49.99万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    7255196
  • 财政年份:
    2007
  • 资助金额:
    $ 49.99万
  • 项目类别:

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