Social Disadvantage and Fetal Programming of Newborn-Infant Telomere Biology

 描述（由申请人提供）：人群健康差异从生命的最早阶段就很明显，在整个生命周期中持续存在，并在几代人之间延续。他们最突出的决定因素是处于社会不利地位。研究已经阐明了社会劣势是如何在生物学上嵌入到整个生命周期中影响疾病风险的，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。我们建议调查的过程中代际（母亲到孩子）传递的社会劣势，重点是新生儿和婴儿的端粒生物学作为主要的结果，宫内期间的传输时间窗口，和母亲-胎盘-胎儿（MPF）的压力生物学作为近端的传输途径。端粒动力学在维持基因组和细胞完整性方面发挥着重要的因果作用，端粒功能障碍可能是常见的年龄相关疾病的疾病风险的最显著的前因细胞表型。动物和人类的研究一致支持端粒的初始（生命早期）设置的至关重要性 端粒酶活性（TA）和端粒长度（TL）对未来健康和疾病风险的影响，但目前对这种初始设置的决定因素知之甚少。我们和其他人发表的和初步的数据为端粒系统的初始设置是可塑的并且受到发育条件的显著影响这一新概念提供了生物学上的合理性。我们假设，在细胞水平上，健康差异的起源可以追溯到，在一定程度上，母亲的社会劣势对她的孩子的端粒长度和端粒酶表达能力的初始设置的影响，介导的“编程”的母亲-胎盘-胎儿（MPF）内分泌，免疫和氧化应激生物学的行动。我们建议在一项前瞻性、纵向队列研究中检验这一假设，该研究对N=1,000名儿童-母亲二人组进行了一系列测量，包括妊娠期和出生至生命的第一年。由于种族/民族和社会经济地位（SES）代表了社会劣势的主要代理指标，并且由于非西班牙裔黑人（以下称为“黑人”）和非西班牙裔白人（以下称为“白人”）之间的健康种族/民族差异最为明显，因此我们拟定的研究人群将包括大约相同数量的黑人和白色母亲及其后代。这一群体的一个独特优势是，社会经济地位的巨大变化不仅在 而且在两个种族/族裔群体内，这将使我们能够摆脱其独立和合并（相互作用）的影响。我们还将评估影响是否因儿童的性别而异。具体目的：A1：检验母体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：验证母体-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影响的假设。A3：识别和量化与社会劣势相关的孕产妇心理、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来自于更好地了解少数弱势群体年龄相关疾病风险的决定因素和机制的重要性（NIA可逆性倡议2012），以告知早期识别和干预的转化研究。

 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.