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.
Disruption of circadian clocks has deleterious effects on the health of most people, especially among the aged, and many of these issues are reflected in deteriorating gastrointestinal health. Further, there is evidence that the pineal hormone melatonin may ameliorate symptoms associated with both sleep: wake cycles and gastrointestinal health in young and old people. This study will determine the mechanisms of circadian patterns of gastrointestinal gene expression and motility in young and old mice and will determine whether decreased melatonin signaling contributes to declining gastrointestinal health. The data may point to future treatments for normal but discomforting gastrointestinal health during aging.