Social Disadvantage and Fetal Programming of Newborn-Infant Telomere Biology

 描述(申请人提供)：人口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，并在几代人之间持续存在。他们最显著的决定因素是暴露在社会劣势中。研究已经阐明了社会劣势如何在生物学上根深蒂固地影响一生中的疾病风险，但对其影响如何世代传播知之甚少。我们的应用程序解决了这一重要差距。我们建议调查社会劣势的代际(母婴)传播过程，重点关注新生儿和婴儿的端粒生物学作为主要结果，宫内时期作为传播时间窗口，母亲-胎盘-胎儿(MPF)应激生物学作为最近的传播途径。端粒动力学在维持基因组和细胞完整性方面起着根本的因果作用，端粒功能障碍可能是常见的年龄相关性疾病的最显著的疾病风险的先兆细胞表型。动物和人类的研究一致支持端粒的初始(早期生命)设置的关键重要性 长度(TL)和端粒酶活性(TA)对未来的健康和疾病风险，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初步数据为端粒系统的初始设置是可塑性的并受到发育条件影响的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，健康差异的起源可能部分追溯到母亲的社会劣势对其子女端粒长度和端粒酶表达能力的初始设定的影响，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”行为调节的。我们建议在一项前瞻性的纵向队列研究中验证这一假设，研究对象为N=1,000名儿童-母亲二元组，通过一系列测量从怀孕到出生到生命的第一年。由于种族/民族和社会经济地位(SES)代表了社会劣势的主要替代衡量标准，而且由于种族/民族在健康方面的差异在非西班牙裔黑人(以下简称为黑人)和非西班牙裔白人(以下简称为白人)之间最为明显，我们提议的研究人群将包括大约相同数量的黑人和白人母亲及其子女。这一群体的一个独特优势是SES的巨大差异，不仅限于 而且是在两个种族/民族群体内部，这将使我们能够摆脱它们的独立和联合(交互)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预期相关的假设。A2：验证母亲-胎盘-胎儿(MPF)应激生物学中介社会劣势对新生儿和婴儿端粒生物学影响的假说。答案3：确定和量化与社会劣势有关的母亲心理、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群体和弱势群体中与年龄有关的疾病风险的决定因素和机制的重要性(NIA可逆性倡议2012)，以便为关于早期识别和干预的转译研究提供信息。

 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.