A central unsolved question in biology is, What coordinates an organism's circadian clocks? Loss of coordination between the central circadian clock in the brain, the suprachiasmatic nucleus (SCN), and circadian clocks in other cells and tissues has been implicated in systems pathologies that lead to sleep disorders. The goal of this discovery proposal is to identify peptides that couple the SCN and [glial] circadian clocks. Studies of peripheral tissues cultured in isolation have revealed that in the SCN's absence, cellular rhythms continue but phase and period properties change in diverse tissues, including brain, liver, lung, muscle, kidney, tail [and spleen]. With decoupling, the various tissue functions lose temporal coherence as well as appropriate alignment to the daily cycle of sleep and wakefulness. Little is known about what couples an organism's circadian clocks, except that diffusible factors are sufficient to entrain many. Discovering coupling factors that communicate time-of-day from SCN to other circadian clocks [in brain and body] has proven difficult. We propose a study applying advanced analytical peptidomic techniques on a micrometer scale coupled with functional determinations of the ability of peptides to restore clock-to-clock coordination, an innovative approach.
We aim to: 1) define and characterize induction of SCN-driven synchronization of [glia] rhythms, 2) identify released candidate coupling peptides by peptidomic analysis, 3) determine the necessity/sufficiency of candidate coupling peptides released from the SCN for inducing synchronous rhythms of [glia] clocks, and 4) characterize and evaluate candidate coupling peptides. Successful completion of these aims will poise us for testing coupling in animal models. Loss of synchrony among internal clocks is maladaptive for health and longevity. There are no current approaches to better synchronize or enhance coupling of the internal clocks. Identifying signals that effectively couple circadian rhythms will have major value in treatment of metabolic syndrome, obesity, cardiovascular stress, and physiological decline with aging, all of which manifest with disordered sleep patterns that affect more than 10 million Americans each year. However, to realize therapeutic potential, signals by which the SCN engages other circadian clocks must be identified and placed in temporal context.
This proposal seeks to identify neuropeptides that provide integration of circadian rhythms in body function across the sleep-wake cycle. Loss of coordination between the central circadian clock in the brain, the suprachiasmatic nucleus (SCN), and circadian clocks in other cells and tissues has been implicated in systems pathologies that lead to sleep disorders, and is maladaptive for health and longevity. Identifying signals that effectively couple circadian rhythms throughout the body will have major value in treatment of metabolic syndrome, obesity, cardiovascular stress, and physiological decline with aging, all of which manifest with disordered sleep patterns that affect more than 10 million Americans each year;however, to realize therapeutic potential, signals by which the SCN engages other circadian clocks must be identified and placed in a temporal context.
|Atkins Jr, Norman; Ren, Shifang; Hatcher, Nathan et al. (2018) Functional Peptidomics: Stimulus- and Time-of-Day-Specific Peptide Release in the Mammalian Circadian Clock. ACS Chem Neurosci 9:2001-2008|
|Gillette, Martha U (2013) Introduction to biological timing in health and disease. Prog Mol Biol Transl Sci 119:xi-xvi|
|Lee, Ji Eun; Zamdborg, Leonid; Southey, Bruce R et al. (2013) Quantitative peptidomics for discovery of circadian-related peptides from the rat suprachiasmatic nucleus. J Proteome Res 12:585-93|
|Wang, Tongfei A; Yu, Yanxun V; Govindaiah, Gubbi et al. (2012) Circadian rhythm of redox state regulates excitability in suprachiasmatic nucleus neurons. Science 337:839-42|
|Yin, Ping; Knolhoff, Ann M; Rosenberg, Harry J et al. (2012) Peptidomic analyses of mouse astrocytic cell lines and rat primary cultured astrocytes. J Proteome Res 11:3965-73|
|Murphy, D; Konopacka, A; Hindmarch, C et al. (2012) The hypothalamic-neurohypophyseal system: from genome to physiology. J Neuroendocrinol 24:539-53|
|Millet, Larry J; Gillette, Martha U (2012) New perspectives on neuronal development via microfluidic environments. Trends Neurosci 35:752-61|
|Mitchell, Jennifer W; Atkins Jr, Norman; Sweedler, Jonathan V et al. (2011) Direct cellular peptidomics of hypothalamic neurons. Front Neuroendocrinol 32:377-86|
|Lee, Ji Eun; Atkins Jr, Norman; Hatcher, Nathan G et al. (2010) Endogenous peptide discovery of the rat circadian clock: a focused study of the suprachiasmatic nucleus by ultrahigh performance tandem mass spectrometry. Mol Cell Proteomics 9:285-97|
|Millet, Larry J; Bora, Adriana; Sweedler, Jonathan V et al. (2010) Direct cellular peptidomics of supraoptic magnocellular and hippocampal neurons in low-density co-cultures. ACS Chem Neurosci 1:36-48|
Showing the most recent 10 out of 12 publications