Early Warning Systems for Childhood and Adult Disorders

项目摘要 根据健康和疾病的发展起源假说，许多疾病起源于 胎儿和出生后早期的环境暴露。这种早期生活环境暴露可以改变 通过破坏一个或多个系统的内稳态，并在这样做的过程中产生 疾病过程或结果的可识别的生物化学特征。然而，缺乏一个 概念框架和技术障碍阻碍了这一领域的研究;因此， 许多疾病直到成年时出现明显的临床症状才被发现，此时它不再是 可能有意义地改变发展或疾病的过程。我们提出了一种新的模式， 将克服这些障碍，在目前的临床和生化测试之前几年发现疾病。通过这样做 我们将能够在疾病出现临床症状之前的几十年预测甚至预防和治疗疾病。的核心 我们的建议是许多人类生理过程的一个未被充分认识的特征--它们通常 在体内平衡时表现出高度时间分辨的生化节律（或周期）。的想法 生物化学节律本身并不是革命性的;睡眠周期，体温，皮质醇节律， 月经周期都是以各种间隔运行的人类生理学的节律性的例子。 然而，医学测试很少考虑节律性。我们不仅要开发一种新技术 分析胎儿发育和儿童期关键生化途径的动态节律性， 准确地检测出明显和持续的体内平衡偏离，这将是晚年的预后 疾病的发病，而且也是一个新的框架，了解发展不仅是一个线性的轨迹， 相互关联的有节奏的过程嵌入在增长轨迹中。

Project Summary According to the developmental origins of health and disease hypothesis, many disorders originate via environmental exposures in fetal and early postnatal life. Such early life environmental exposures can alter the developmental trajectory by disrupting the homeostasis of one or more systems, and in doing so produce identifiable biochemical signatures characteristic of the disease process or outcome. However, the lack of a conceptual framework as well as technological barriers have hampered research in this area; consequently, many disorders are not detected until overt clinical signs appear in adulthood, at which point it is no longer possible to meaningfully alter the course of development or disease. We are proposing a new paradigm that will overcome these barriers to detect disease years before current clinical and biochemical tests. By doing so we will be able to predict, and even prevent and treat diseases decades before any clinical signs. Central to our proposal is an underappreciated characteristic of many human physiologic processes—they commonly exhibit highly temporally resolved biochemical rhythms (or cycles) when at homeostasis. The idea of biochemical rhythms in itself is not revolutionary; sleep cycles, body temperature, cortisol rhythms, and menstrual cycles are all examples of the rhythmic nature of human physiology operating at various intervals. Medical testing, however, seldom considers rhythmicity. We propose to develop not just a novel technology that analyzes dynamic rhythmicity of key biochemical pathways during fetal development and childhood to accurately detect marked and sustained deviations from homeostasis that would be prognostic of later-life disease onset, but also a new framework for understanding development not solely as a linear trajectory but as interconnected rhythmic processes embedded within the growth trajectory.