Circadian Involvements in Mental Health – Prognostic and Therapeutic Prospects
Mental illnesses are one of the significant causes of disease burden. Chronic disruption of circadian control has widespread effects on all aspects of neural and neuro-endocrine functions. The central hypothesis of this project is that the circadian clock plays a significant role in mental health, and the aberrations in clock machinery are linked with various mood disorders. The circadian dysfunctions in a major mood disorder, bipolar disorder (BD), at the molecular level, have not been investigated adequately. In this project, we intend to compare the circadian amplitude parameter in BD patients measured by actigraphy and by rhythmic expression or abundance of core clock genes and metabolites. We want to understand whether the actigraphic risk index predicts relapse in BD patients. We also intend to understand the circadian control of pathogenic disease factors and therapeutic drug targets to get insights into the impact of dosing time on the efficacy of the drugs currently used for treating mental and neurological disorders. We expect to decipher the importance of the circadian time-keeping system as a therapeutic target for mental disorders and the mechanism of actions of mood stabilization and clock enhancement-based therapeutics.
Cross-talk among Circadian Disruption, Sleep Deficiency, and Aging
Sleep-related disorders are increasing rapidly in modern society worldwide. Aging and sleep deficiency are variables that can perturb circadian clock regulation and potentially increase the risk for diverse chronic diseases. With growing age, our unequivocal time-keeping machinery most likely breaks down, leading to lower adaptability to the periodic changes in the environment and disruptions in the circadian rhythm. Observable alterations in sleep-wake cycles, such as the advanced onset of sleep, disintegrated sleep, and reduced sleep quality, also accompany aging. That explains the quintessential existence of an incomprehensible yet tangible relationship between aging, sleep disorders, and circadian rhythms. Hence, understanding the complex interplay among the circadian clock, sleep deficiency, and aging is essential for unfurling mechanistic insight into geriatric health problems. We hypothesize that aberrations in circadian rhythmicity could be a common mechanism for diverse age-induced ailments. We aim to decode healthy aging by providing accurate circadian measures or predictors through cutting-edge omics-based high throughput technologies. We intend to illustrate the effects of sleep deprivation on circadian rhythmicity and whether the adversity of sleep deficiency and DNA damage is influenced by aging.
Dosing Time Dependency of Anticancer Drugs and Their Effects on Circadian Clock Machinery
Intrinsic rhythms in host and cancer cells play an imperative role in tumorigenesis and anticancer therapy. Clock gene expressions are frequently altered in cancers, specifically in high-grade aggressive tumors, and disruptions of clock machinery may lead to poor prognosis in cancer patients. Circadian medicine in cancer is principally reliant on controlling the growth and development of cancer cells or tissues by targeting the molecular clock and implementing time-of-day-based anticancer treatments for therapeutic improvements. Dosing time for anticancer drugs can impact their overall efficacy, particularly for candidates with shorter half-lives. Therefore, understanding the rhythmic expressions of proteins involved in the pharmacokinetics and pharmacodynamics of anticancer therapeutics is very important. In this project, we are investigating the dosing time dependency of anticancer drugs (breast cancer, colorectal cancer, and retinoblastoma) and their metabolic pathways. We are also interested in understanding the molecular mechanisms and cellular responses of novel pharmacological modulators of the mammalian circadian clock with potential anticancer properties.
Host and Parasite Rhythms in Malaria to Decipher its Cyclic Nature of Disease Pathogenesis
Malaria is the world's most significant tropical infectious disease, representing a substantial cause of infection-associated mortality worldwide. Management of malaria is still a crucial global challenge due to its complex pathogenesis and emerging resistance to most of the existing antimalarial drugs. The cyclical nature of malaria is well documented, as the infection cycles for Plasmodium species that infect humans last a multiple of approximately 24 hours. Clock-infection biology may be vital in malaria pathogenesis, infection severity, and treatment. In this project, we systematically investigate the circadian proteome and metabolome of the in-vitro cultured Plasmodium falciparum 3D7 strain and non-severe and severe falciparum malaria patients' serum and RBC using mass spectrometry-based approaches. We evaluate the effects of pharmacological agonists of circadian clocks on parasitemia in P. falciparum culture. We also study the rhythmic expressions of molecular targets and receptors of widely used antimalarials using various in-silico approaches to evaluate their possible dosing time dependency.
Circadian Disruptions in Cardiovascular Diseases and Circadian Regulation of Cardiac Medicine
Acute myocardial infarction and coronary ischemic heart diseases comprise the most significant portion of disability-adjusted life years related to cardiovascular diseases (CVDs). The circadian clock regulates several cardiovascular processes, including blood pressure, heart rate, thrombus development, and endothelial function. Coronary artery diseases such as myocardial infarction can be correlated with the consequences of circadian time-keeping system dysfunction. The circadian machinery could directly or indirectly influence any drug's pharmacokinetics, pharmacodynamics, and therapeutic index. Therefore, circadian regulations are essential for formulating and administering medications for cardiovascular diseases. In this project, our research strategy focuses on unraveling circadian regulation and anomalies in young and elderly CVD patients. We investigate the physiological and biochemical measures of diurnal rhythmicity in heart disease patients. Additionally, we aim to demonstrate the rhythmic expression of primary molecular targets for widely prescribed cardiac medications to assess potential dosing time dependence (regarding therapeutic efficacy and side effects).
Circadian Regulations of Kinases and Diverse Signaling Pathways
Protein kinases and signaling pathways are currently one of the most important pharmacological targets since abnormal phosphorylation is a cause or consequence of numerous human diseases, including cancers. Circadian regulation of kinases and signaling pathways is mostly undefined. The deletion of the core clock components disrupts regular physiological and metabolic activities. However, the circadian clocks' direct regulations of kinases, signaling molecules, and different signaling networks are not thoroughly characterized in the fruit fly or mammals. This project uses an integrated quantitative proteomics pipeline to investigate the circadian regulations in the expression and activity profiles of kinases and their associated signaling pathways. This project will provide insights regarding the individual and collective roles of the clock machinery in maintaining daily rhythmicity in signaling cascades and phosphorylation networks central to sustaining regular physiological functions.
Prof. Anindya Roy
Dr. Rahul Kumar
Dr. Neeraj Kumar
Dr. Aravind Kumar Rengan
Prof. Arunansu Talukdar
Medical College Kolkata
Prof. G. Narahari Sastry
CSIR, North East Institute of Science and Technology
Dr. Abhishek Mohanty
Continental Hospitals, Hyderabad
Dr. Jyothirmayi Kotipalli
Continental Hospitals, Hyderabad
Prof. Greg Murray
Swinburne University of Technology, Melbourne, Australia
Prof. Richard Porter
University of Otago, Christchurch
Prof. Jann Scott
Newcastle University, UK