Circadian rhythms and melatonin signaling in the aging gastrointestinal system

描述（由申请人提供）：生物钟是所有详细研究的生物体的基本特性。在动物中，生物钟调节着 睡眠：唤醒周期，以及内部身体功能的协调，如温度、激素水平、疾病和胃肠道生理学方面的时间变化。生物节律的分子基础至少部分受到“时钟基因”表达的调控，这是一组基因，它们复杂的相互作用控制着24小时的节律。我们实验室的工作表明，时钟基因在调节结肠运动中很重要：小鼠结肠具有功能性昼夜节律钟，可调节各种基因的节律以及肠道运动。此外，我们已经表明，结肠时钟调节与正常肠道运动，吸收，细胞增殖和细胞信号传导以及潜在的病理过程相关的多个下游过程。此外，在哺乳动物中，有一个分层组织，其中下丘脑视交叉上核（SCN）中的中央起搏器协调多个外周过程，并通过专门的光通路将整个系统带入光暗周期（LD）。我们的一般假设是，胃肠道昼夜节律的整体调节涉及中央SCN钟表机构和肠道时钟本身的复杂双向相互作用，并且这些中的任何一个被破坏都会使我们容易患病。这项建议的总体目标是确定结肠运动在正常情况下随时间变化的潜在机制，并确定衰老对结肠运动昼夜节律模式的影响。我们的假设是，一个因素介导的变化，在肠道功能老化是昼夜分泌的激素褪黑激素的松果体和肠道组织本身。因此，我们将探讨正常衰老对胃肠道节律的哪些方面产生影响（具体目标1）。然后，我们将询问松果体褪黑激素是否在几个生物组织水平上影响年轻与老年小鼠的胃肠节律。最后，我们将通过比较褪黑激素缺乏的小鼠品系（C57/B16）与能够产生褪黑激素周期的小鼠品系（C3 H）来询问褪黑激素产生中的干扰是否影响胃肠节律的老化方面，以及通过比较野生型与MT 1受体、MT 2受体和MT 2/MT 2受体敲除小鼠来询问这些过程是否依赖于已知的褪黑激素受体分子。

DESCRIPTION (provided by applicant): Biological circadian clocks are fundamental properties of all living organisms studied in any detail. In animals, clocks regulate the timing of sleep: wake cycles, as well as the coordination of internal body functions, such as temporal variations in temperature, hormone levels, aspects of disease and gastrointestinal physiology. The molecular bases for biological rhythms are at least in part regulated by the expression of "clock genes", a group of genes whose complex interactions govern 24-hour rhythms. Work in our lab has demonstrated that clock genes are important in the regulation of colonic motility: the mouse colon possesses a functional circadian clock that regulates rhythms of a wide array of genes as well as intestinal motility. Further, we have shown that the colonic clock regulates multiple downstream processes associated with normal intestinal motility, absorption, cell proliferation and cell signaling as well as potential pathological processes. In addition, in mammals, there is a hierarchical organization in which a central pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) coordinates multiple peripheral processes as well as entrains the entire system to the light: dark cycle (LD) through specialized photic pathways. Our general hypothesis is that the global regulation of gastrointestinal circadian rhythms involves the complex, bi-directional interaction of central SCN clockworks and intestinal clocks themselves, and that disruption of any of these predisposes us to disease. The overall objective of this proposal is to determine the underlying mechanism through which colonic motility varies with the time of day under normal circumstances and to determine the consequences of aging on circadian patterns of colonic motility. Our hypothesis is that one factor mediating changes in intestinal function during aging is the circadian secretion of the hormone melatonin by the pineal gland and by intestinal tissues themselves. We will therefore ask what aspects of gastrointestinal rhythms are affected by normal aging (Specific Aim 1). We will then ask whether pineal melatonin influences gastrointestinal rhythmicity in young vs aged mice at several levels of biological organization. Finally, we will ask whether interference in the production of melatonin affects aging aspects of gastrointestinal rhythmicity by comparing melatonin deficient strains of mice (C57/Bl6) with strains of mice capable of producing melatonin cycles (C3H) and whether these processes are dependent the known melatonin receptor molecules by comparing wild-type with MT1 receptor, MT2 Receptor and MT2/MT2 receptor knockout mice.