Early Warning Systems for Childhood and Adult Disorders

项目摘要 根据健康和疾病的发育起源假说，许多疾病起源于 胎儿和出生后早期的环境暴露。这种早期的生活环境暴露会改变 通过破坏一个或多个系统的动态平衡的发展轨迹，并在这样做的过程中产生 疾病过程或结果的可识别的生化特征。然而，缺乏一种 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，在这一点上，它不再是 有可能有意义地改变发展或疾病的进程。我们正在提出一种新的模式， 将克服这些障碍，在目前的临床和生化测试之前数年发现疾病。通过这样做 我们将能够在任何临床症状出现前几十年预测、甚至预防和治疗疾病。中心到 我们的建议是许多人类生理过程中被低估的特征--它们通常 当处于动态平衡时，表现出高度时间分辨的生化节律(或周期)。这个想法是 生化节律本身并不是革命性的；睡眠周期、体温、皮质醇节律以及 月经周期都是以不同的时间间隔运行的人类生理节律性的例子。 然而，医学测试很少考虑节奏性。我们建议开发的不仅仅是一项新技术 分析胎儿发育和儿童时期关键生化途径的动态节律性，以 准确地检测出显著和持续的动态平衡偏离，这将是未来生活的预测 疾病的发生，而且是一个新的框架，不仅将发育理解为线性轨迹，还将其理解为 嵌入增长轨迹的相互关联的节奏过程。

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.