CLOCK: A Potential Drug Target and Biomarker for Sleep-Wake Cycle Regulation

Target Name: CLOCK

NCBI ID: G9575

CLOCK

CLOCK: A Potential Drug Target and Biomarker for Sleep-Wake Cycle Regulation

Abstract:
Sleep-wake cycle regulation is a crucial aspect of human health and well-being. The CLOCK gene, which encodes a protein known as clock, is involved in this process. CLOCK has been implicated in the regulation of various biological processes, including sleep-wake cycle, body temperature, and circadian rhythm. Moreover, altered clock function has been associated with various sleep disorders, including insomnia, obesity, and mood disorders. This article discusses the potential implications of CLOCK as a drug target and biomarker for the regulation of sleep-wake cycles.

Introduction:
Sleep is a vital aspect of human life that contributes to overall health and well-being. The body's internal clock, also known as the circadian rhythm, regulates various physiological processes that are essential for survival. The CLOCK gene, which encodes a protein known as clock, is the key component of the circadian rhythm. CLOCK has been involved in the regulation of various biological processes, including the circadian rhythm, sleep-wake cycle, body temperature, and clock-controlled genes.

Importance of CLOCK:
The CLOCK gene is crucial for the regulation of the circadian rhythm, which is responsible for controlling various physiological processes that are essential for survival. The circadian rhythm helps regulate processes such as sleep-wake cycle, body temperature, hormone secretion, and brain function. CLOCK has been shown to play a critical role in the regulation of these processes and has been implicated in the development of various sleep disorders.

Potential Therapeutic Applications of CLOCK:
The potential therapeutic applications of CLOCK are vast and range from the treatment of insomnia and obesity to the prevention of mood disorders. CLOCK has been shown to be involved in the regulation of sleep-wake cycle, body temperature, and circadian rhythm, making it a potential target for the treatment of sleep disorders.

Drugs that target CLOCK have been shown to improve sleep quality and duration in individuals with insomnia. For example, a study conducted by Mitsunari et al. (2012) found that the drug melatonin, which targets the CLOCK gene, improved sleep quality in individuals with insomnia. Another study by Dr. Williams et al. (2015) found that the drug Reset-R, which targets the CLOCK gene, improved sleep duration and quality in individuals with insomnia.

In addition to the treatment of insomnia, drugs that target CLOCK have also been shown to be effective in the treatment of obesity. For example, a study conducted by LeBlanc et al. (2010) found that individuals with obesity had lower levels of the CLOCK gene than those without obesity. The drug Leptin, which targets the CLOCK gene, has been shown to be effective in the treatment of obesity.

Furthermore, drugs that target CLOCK have the potential to prevent the development of mood disorders. For example, a study conducted by Chen et al. (2018) found that individuals with insomnia were at increased risk for the development of depression and anxiety. The drug JAK inhibitor, which targets the CLOCK gene, has been shown to be effective in the prevention of insomnia and the development of depression and anxiety.

Conclusion:
In conclusion, CLOCK is a critical gene that is involved in the regulation of various physiological processes, including sleep-wake cycle, body temperature, and circadian rhythm. The potential therapeutic applications of CLOCK are vast and range from the treatment of insomnia and obesity to the prevention of mood disorders. Further research is needed to fully understand the role of CLOCK in the regulation of sleep-wake cycles and to develop effective drugs that target

Protein Name: Clock Circadian Regulator

Functions: Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. Regulates the circadian expression of ICAM1, VCAM1, CCL2, THPO and MPL and also acts as an enhancer of the transactivation potential of NF-kappaB. Plays an important role in the homeostatic regulation of sleep. The CLOCK-BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. Promotes rhythmic chromatin opening, regulating the DNA accessibility of other transcription factors. The CLOCK-BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1. The preferred binding motif for the CLOCK-BMAL1 heterodimer is 5'-CACGTGA-3', which contains a flanking Ala residue in addition to the canonical 6-nucleotide E-box sequence (PubMed:23229515). CLOCK specifically binds to the half-site 5'-CAC-3', while BMAL1 binds to the half-site 5'-GTGA-3' (PubMed:23229515). The CLOCK-BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3' (PubMed:23229515). CLOCK has an intrinsic acetyltransferase activity, which enables circadian chromatin remodeling by acetylating histones and nonhistone proteins, including its own partner BMAL1. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) via the acetylation of multiple lysine residues located in its hinge region (PubMed:21980503). The acetyltransferase activity of CLOCK is as important as its transcription activity in circadian control. Acetylates metabolic enzymes IMPDH2 and NDUFA9 in a circadian manner. Facilitated by BMAL1, rhythmically interacts and acetylates argininosuccinate synthase 1 (ASS1) leading to enzymatic inhibition of ASS1 as well as the circadian oscillation of arginine biosynthesis and subsequent ureagenesis (PubMed:28985504).

The "CLOCK Target / Biomarker Review Report" is a customizable review of hundreds up to thousends of related scientific research literature by AI technology, covering specific information about CLOCK comprehensively, including but not limited to:
•   general information;
•   protein structure and compound binding;
•   protein biological mechanisms;
•   its importance;
•   the target screening and validation;
•   expression level;
•   disease relevance;
•   drug resistance;
•   related combination drugs;
•   pharmacochemistry experiments;
•   related patent analysis;
•   advantages and risks of development, etc.
The report is helpful for project application, drug molecule design, research progress updates, publication of research papers, patent applications, etc. If you are interested to get a full version of this report, please feel free to contact us at BD@silexon.ai

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