Circadian rhythms and melatonin signaling in the aging gastrointestinal system

描述(由申请人提供)：生物生物钟是所有被详细研究的生物的基本特性。在动物身上，时钟调节着 睡眠：清醒周期，以及身体内部功能的协调，如温度、激素水平、疾病方面和胃肠生理的时间变化。生物节律的分子基础至少部分受“时钟基因”的表达调控，“时钟基因”是一组基因，其复杂的相互作用控制着24小时的节律。我们实验室的工作已经证明时钟基因在结肠运动的调节中很重要：小鼠的结肠拥有一个功能强大的生物钟，它调节一系列基因的节奏以及肠道运动。此外，我们已经证明，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，下丘脑视交叉上核(SCN)中的中央起搏器协调多个外周过程，并通过特殊的光通路将整个系统带入光：暗周期(LD)。我们的一般假设是，胃肠道昼夜节律的全球调节涉及中枢SCN时钟和肠道时钟本身复杂的双向相互作用，其中任何一个的干扰都会使我们容易患病。这项建议的总体目标是确定正常情况下结肠运动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，在衰老过程中，调节肠道功能变化的一个因素是松果体和肠道组织本身对褪黑激素的昼夜分泌。因此，我们将询问正常衰老影响胃肠节律的哪些方面(具体目标1)。然后，我们将询问松果体褪黑素是否在生物组织的几个水平上影响年轻和老年小鼠的胃肠节律。最后，我们将通过比较褪黑素缺乏的小鼠品系(C57/BL6)和能够产生褪黑素周期(C3H)的小鼠品系，以及通过比较野生型与MT1受体、MT2受体和MT2/MT2受体敲除小鼠，这些过程是否依赖于已知的褪黑素受体分子，来询问干扰褪黑素的产生是否影响胃肠节律性的衰老方面。

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.