Key Dates

Related Announcements

PA-20-183 - Research Project Grant (Parent R01 Clinical Trial Required)

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

Issued by

National Heart, Lung, and Blood Institute (NHLBI)

Purpose

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.

Specific examples of potential research directions under this program at the National Heart, Lung and Blood Institute include but are not limited to the following:

• Apply contemporary genomic, biochemical, and molecular tools to interrogate circadian signaling (including transcription, translation, and post-translational modification) in cells and tissues relevant to HLBS disease research.
• Elucidate molecular mechanisms regulating expression and function of ion channels and receptors that contribute to ionic imbalances and signaling associated with normal and abnormal cardiovascular function and premature mortality.
• Determine the mechanisms mediating circadian synchronization within cells and peripheral tissues, the abnormalities in synchronization associated with heart, lung, and blood disease susceptibility, and the potential strategies to restore circadian synchronization in affected tissues and ameliorating disease risk or prognosis.
• Elucidate the circadian periodicity in cardiomyocyte metabolism and its relationship to cardiac contractility, cardiac pacing, and mechanisms of disease pathogenesis such as heart failure, arrhythmia and the genomic responses to ischemia.
• Elucidate the circadian periodicity in vascular endothelial function and reactivity in relationship to the pathogenesis of vascular disease through mechanisms such as inflammation, behavioral stress, and abnormalities in lipid metabolism.
• Investigate the circadian-dependent lung cellular function in relationship to exacerbations of asthma, cystic fibrosis, COPD and IPF—including but not limited to circadian clock control of viral/bacterial and/or fungal infections.
• Identify neurons, pathways, signals and mechanisms regulating circadian-dependent hematopoiesis, hematopoietic stem cell migration, blood cell function and thrombosis in normal and in stressed situations.
• Generate diverse animal models for circadian rhythms as well as for chronotherapy and determine how innate circadian rhythms interact with and modify the physiological responses and how perturbations in circadian rhythms can impact health risk in animal models.
• Develop and validate biomarkers to assess behavioral, central, and peripheral (including cardiac) circadian rhythms and assess correlations with HLBS disease risk. Determine if biomarkers that reflect circadian disruption are robust predictors of HLBS diseases and whether restoring circadian rhythm lowers risk of such diseases.
• Investigate the impact of timing for feeding, exercise, and drug administration on alleviating risk in HLBS disorders.

• Identify and investigate subsets of at-risk persons distinguished by sex/gender, race, age, cardiovascular, lung and hematologic pathology, treatments, genetics, circadian disruption, etc. and determine in which subsets physiological changes across the circadian cycle confer HLBS disease risk.
• Use of established NHLBI resources with large-scale human data sets (TOPMed, BioData Catalyst, existing HLBS cohorts) to correlate chronobiological measurements to hematologic, lung and/or cardiovascular outcomes.
• Use existing data sets from wearable devises, bioinformatics and artificial intelligence (AI) to interrogate day-night rhythmic phenotypes and improve measurement of blood pressure, circadian rhythm, sleep and their inter-relationships.
• Determine how innate circadian rhythms interact with and modify responses to extrinsic triggers of HLBS diseases to create timing of disease-specific treatments with circadian-dependent phenomena to achieve optimal therapeutic and preventive effects.
• Investigate circadian rhythms of gut microbiota and their effects on HBLS disorders.

Application and Submission Information

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

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

• PA-20-183 - NIH Research Project Grant (Parent R01 Clinical Trial Required) (Mechanistic trials only)
•  PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

NOTE: NHLBI will accept applications to PA-20-183 - NIH Research Project Grant (Parent R01 Clinical Trial Required) if they propose mechanistic studies that meet NIH’s definition of a clinical trial and that have the primary goal of understanding how an intervention works per guidance in NOT-HL-19-690. Applicants are strongly encouraged to consult the NHLBI Scientific/Research Contact listed below prior to submission to confirm the NHLBI-specific clinical trial FOA to which the application should be submitted.

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-HL-22-043” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Scientific/Research Contact(s)
 

Ravi Balijepalli, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Division of Cardiovascular Sciences
Telephone: 301-435-0504
Email:ravi.balijepalli@nih.gov

Brian Bai, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Division of Blood Diseases and Resources
Telephone: 301-827-5212
Email:brian.bai@nih.gov

Marrah Lachowicz-Scroggins, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Division of Lung Diseases
Telephone: 301-827-8229
Email:marrah.lachowicz-scroggins@nih.gov

Aaron Laposky, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
National Center on Sleep Disorders Research
Telephone: 301-827-7837
Email:laposkya@nhlbi.nih.gov

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

E-Bijan Cox
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-480-8628
Email: e-bijan.cox@nih.gov