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Notice of Special Interest (NOSI): Basic and Translational Research on Circadian Regulation of Heart, Lung, Blood, and Sleep Disorders (R01)

National Institutes of Health

Circadian rhythms are driven by an internal biological clock that anticipates day/night cycles to optimize the physiology and behavior of organisms. These 24-hour patterns set our clocks for specific times of eating and sleeping, as well as optimal times for many other basic functions. Circadian regulation of gene expression and cellular function has been reported in nearly all tissues that have been implicated in the pathogenesis of heart, lung, blood and sleep diseases. Circadian rhythm misalignment, resulting from irregular or insufficient sleep schedules, biologically inappropriate light exposure, and diet-associated zeitgebers pose an emerging risk to health world-wide. In the U.S., 30-40% of adults and 40-70% of adolescents report symptoms of poor circadian and sleep health annually. Additionally, circadian variations result in the increased frequency of heart attacks and arrhythmia, the severity of ischemic myocardial injury and bronchial responsiveness, and levels of inflammation factors have been observed, but the underlying molecular mechanisms are not clearly understood. Recent advances indicate that the fundamental cellular metabolism (e.g., mitochondrial oxidation state, glucose metabolism, fatty acid oxidation) and pathophysiology (e.g., oxidative/endoplasmic reticulum stress, impaired insulin secretion, inflammation, neurohormones) are circadian- regulated. Common pharmacotherapies for heart, lung, and blood diseases influence the expression of clock genes, but the implications of these modulations in disease have not been well studied. Many fundamental basic science questions remain unanswered regarding the mechanisms by which circadian clocks impact cardiovascular, lung and blood systems physiology. More investigation is needed to understand how circadian clocks function in different cell types (e.g., cardiomyocytes, endothelial cells, fibroblasts, immune cells, hematopoietic stem cells, platelets, and neurons) to influence the function of the heart, lung, blood and autonomic nervous system. Identifying disruptions in circadian rhythms associated with vulnerability to diseases such as heart failure, arrhythmias, sudden cardiac death, hypertension, asthma, idiopathic pulmonary fibrosis (IPF), thrombosis, hematopoietic, and sleep disorders could lead to new targets for preventative and chronotherapeutic strategies for drug administration and delivery to correct disrupted rhythms that confer risks to the HLBS system. Several challenges to exploring these questions are rooted in the limitations of both animal and cellular models, as well as of clinical research.

This NOSI aims to stimulate research on understanding how circadian rhythms regulate cell function and metabolism of peripheral tissues, and to find new avenues for the investigation of heart, lung, and blood disease risk, pathogenesis, diagnosis, treatment, and prevention. Basic, translational, and clinical research applications to elucidate circadian-dependent mechanisms contributing to the pathophysiology of HLBS disorders are invited. This NOSI encourages multidisciplinary and multiple investigator teams of experts in heart, lung, and blood research fields to synergistically work with circadian biologists and sleep researchers to provide a comprehensive understanding of the circadian biology in relation to HLBS conditions. The purpose is to facilitate translational research to identify potential applications of circadian science to the diagnosis, prevention and treatment of HLBS conditions. Mechanism-based studies investigating the circadian rhythm dysregulation, clinical markers, and/or therapeutic targets of HLBS conditions are encouraged. Behavioral, physiological, pharmacological, molecular, and genomic studies aimed at elucidating the relationship between circadian-dependent mechanisms and disease are appropriate. Studies to delineate circadian-based mechanisms, therapeutic targets, epidemiological risk and clinical trials to assess therapeutic safety, efficacy, effectiveness, or implementation may be proposed.

This notice applies to due dates on or after January 25, 2023 and subsequent receipt dates through January 7, 2028.

NOT-HL-22-043