Social Disadvantage and Fetal Programming of Newborn-Infant Telomere Biology

新生儿端粒生物学的社会劣势和胎儿编程

• 批准号: 9105960
• 负责人: ELIZABETH H BLACKBURN
• 金额: $ 67.24万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9105960
• 关键词: Accounting; Address; Alcohol or Other Drugs use; Animals; Attenuated; Back; Behavioral; Biological; Biological Markers; Biological Process; Biology; Birth; Birth Weight; Cellular biology; Characteristics; Child; Child Development; Classification; Cohort Studies; Conceptions; Data; Development; Diet; Disadvantaged; Discipline of obstetrics; Discrimination; Disease; Early Intervention; Early identification; Endocrine; Equation; Ethnic Origin; Ethnic group; Exposure to; Food; Functional disorder; Future; Generations; Genomics; Genotype; Gestational Age; Goals; Graph; Growth; Health; Hematopoietic; Human; Hydrocortisone; Immune; Infant; Infection; Interleukin-6; Interpersonal Violence; Intervention; Isoprostanes; Length; Leukocytes; Life; Longevity; Maintenance; Maternal Age; Maternal and Child Health; Measures; Mediating; Mediation; Minority; Mitogens; Modeling; Mothers; National Institute on Aging; Newborn Infant; Not Hispanic or Latino; Oxidative Stress; Paternal Age; Pathway Analysis; Pathway interactions; Peripheral Blood Mononuclear Cell; Phenotype; Physical activity; Play; Population; Pregnancy; Process; Protocols documentation; Proxy; Public Health; Publishing; Race; Research; Risk; Role; Skin; Sleep; Social support; Societies; Socioeconomic Status; Staging; Stress; Subgroup; System; Systems Biology; Telomerase; Testing; Time; Translational Research; Trees; Validation; Variant; Vertical Disease Transmission; Vulnerable Populations; age related; base; biophysical properties; burden of illness; disadvantaged population; disorder risk; ethnic difference; ethnic minority population; feeding; fetal; fetal programming; gestational weight gain; health difference; health disparity; intergenerational; man; maternal stress; novel; offspring; pediatric trauma; population health; postnatal; prenatal stress; primary outcome; programs; prospective; psychologic; public health relevance; racial and ethnic; racism; sex; social; socioeconomic disadvantage; study population; telomere; transmission process

 DESCRIPTION (provided by applicant): Population health disparities are evident from the earliest stages of the life, persist over the life span, and are perpetuated across generations. Their most salient determinant is exposure to social disadvantage. Research has elucidated how social disadvantage gets biologically embedded to impact disease risk over the life span, but little is known about how its effects are transmitted across generations. Our application addresses this important gap. We propose to investigate the process of intergenerational (mother-to-child) transmission of social disadvantage, with a focus on newborn and infant telomere biology as the primary outcome, the intrauterine period as the transmission time window, and maternal-placental-fetal (MPF) stress biology as the proximate transmission pathway. Telomere dynamics play a fundamental, causal role in the maintenance of genomic and cellular integrity, and telomere dysfunction represents perhaps the most salient antecedent cellular phenotype of disease risk for common, age-related disorders. Animal and human studies converge to support the critical importance of the initial (early life) setting of telomere length (TL) and telomerase activity (TA) for future health and disease risk, but little is currentl known about the determinants of this initial setting. Published and preliminary data by us and others provides biological plausibility for the novel concept that the initial setting of the telomre system is plastic and substantially influenced by developmental conditions. We hypothesize that, at the cellular level, the origins of health disparities may trace back, in part, to the effets of maternal social disadvantage on the on the initial setting of her child's telomere length and telomerase expression capacity, mediated by the "programming" actions of maternal-placental-fetal (MPF) endocrine, immune and oxidative stress biology. We propose to test this hypothesis in a prospective, longitudinal cohort study of N=1,000 child-mother dyads with serial measures across gestation and birth through the first year of life. Because race/ethnicity and socioeconomic status (SES) represent the principal proxy measures of social disadvantage, and because racial/ethnic differences in health are most pronounced between Non-Hispanic Blacks (hereinafter `Black') and Non-Hispanic Whites (hereinafter `White'), our proposed study population will include approximately equal numbers of Black and White mothers and their offspring. A unique strength of this population is the substantial variation in SES not only across but also within the two racial/ethnic groups, which will enable us to extricate their independent and combined (interaction) effects. We also will evaluate whether effects vary by the sex of the child. Specific Aims: A1: To test the hypothesis that maternal social disadvantage is prospectively associated with newborn and infant telomere biology. A2: To test the hypothesis that maternal-placental-fetal (MPF) stress biology mediates the effects of social disadvantage on newborn and infant telomere biology. A3: Identify and quantify the maternal psychological, behavioral and biophysical characteristics that are associated with social disadvantage and may account for its impact on newborn and infant telomere biology. The significance and impact of this study derives from the importance of better understanding the determinants and mechanisms underlying age-related disease risk in minority, disadvantaged populations (NIA Reversibility Initiative 2012) to inform translational research on early identification and intervention.

 描述（由申请人提供）：人口健康差异从生命的最初阶段就很明显，在整个生命周期中持续存在，并且在几代人之间持续存在。他们最显着的决定因素是处于社会劣势。研究已经阐明了社会劣势如何在生物学上嵌入并影响一生中的疾病风险，但对其影响如何跨代传播却知之甚少。我们的应用程序解决了这一重要差距。我们建议研究社会劣势的代际（母婴）传播过程，重点关注新生儿和婴儿端粒生物学作为主要结果，宫内期作为传播时间窗口，母体-胎盘-胎儿（MPF）应激生物学作为最近传播途径。端粒动力学在维持基因组和细胞完整性中发挥着基本的因果作用，端粒功能障碍可能代表了常见的年龄相关疾病风险的最显着的先行细胞表型。动物和人类研究一致支持端粒初始（生命早期）设置的至关重要性 长度（TL）和端粒酶活性（TA）对未来健康和疾病风险的影响，但目前对这一初始设置的决定因素知之甚少。我们和其他人发表的初步数据为端粒系统的初始设置是可塑的并且很大程度上受发育条件影响的新概念提供了生物学合理性。我们假设，在细胞水平上，健康差异的根源可能部分追溯到母亲的社会劣势对其孩子端粒长度和端粒酶表达能力初始设定的影响，这是由母体-胎盘-胎儿（MPF）内分泌、免疫和氧化应激生物学的“编程”作用介导的。我们建议通过一项前瞻性纵向队列研究来检验这一假设，该研究对 N=1,000 名儿童-母亲二人组进行了从妊娠到出生直至生命第一年的一系列测量。由于种族/族裔和社会经济地位（SES）代表了社会劣势的主要代理指标，并且由于健康方面的种族/族裔差异在非西班牙裔黑人（以下简称“黑人”）和非西班牙裔白人（以下简称“白人”）之间最为明显，因此我们提议的研究人群将包括数量大致相等的黑人和白人母亲及其后代。该人群的独特优势在于社会经济地位的巨大差异，不仅在不同地区 而且还存在于两个种族/族裔群体之内，这将使我们能够摆脱它们的独立和组合（相互作用）影响。我们还将评估影响是否因孩子的性别而异。具体目标： A1：检验母亲的社会劣势与新生儿和婴儿端粒生物学前瞻性相关的假设。 A2：检验母体-胎盘-胎儿（MPF）应激生物学介导社会劣势对新生儿和婴儿端粒生物学的影响的假设。 A3：识别并量化与社会劣势相关的母亲心理、行为和生物物理特征，并可能解释其对新生儿和婴儿端粒生物学的影响。这项研究的意义和影响源于更好地了解少数弱势群体中年龄相关疾病风险的决定因素和机制的重要性（NIA Reversibility Initiative 2012），为早期识别和干预的转化研究提供信息。