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            <div class="field field--name-field-banner-description field--type-string-long field--label-hidden field__item">Critical opportunities as presented are timely and actionable research directions with the potential for high impact over the next decade.</div>
      
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            <div class="field field--name-field-component-section-desc field--type-text-long field--label-hidden clearfix field__item"><p>This plan identifies timely and actionable research approaches with the potential to significantly impact sleep, circadian, and biomedical sciences that were identified across the translational spectrum – from knowledge generation and discovery science to medicine and public health. These opportunities map to multiple strategic goals and were selected as examples that inform the overall research agenda. These opportunities do not exclude other research directions or limit the consideration of any investigator-initiated line of study.</p></div>
      
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<h2 class="field--name-field-component-section-titl component-section-section-title">CO1: Identify biomarkers in sleep and circadian physiology to indicate the severity of medical conditions and the effectiveness of therapeutic interventions.</h2>

            <div class="field field--name-field-component-section-desc field--type-text-long field--label-hidden clearfix field__item"><p><img alt="laboratory test tubes. Decorative" data-entity-type="file" data-entity-uuid="cc979e96-f7d2-4d45-9e2e-d293cbc0e7f4" data-image-style="" height="268" width="401" class="align-left b-lazy" data-src="/sites/default/files/inline-images/shutterstock_1706404348_resize_0.jpg" src="/modules/custom/nhlbi_blazy/images/clear.png" />Molecular and cellular indicators of normal biological processes, disease processes, and responses to an exposure or intervention (biomarkers) are critical to translating advances in sleep and circadian science, as well as medical and public health applications. Objective tools to efficiently measure the magnitude of genomic and clinical abnormalities associated with sleep deficiency and poor circadian health enable the discovery of potentially modifiable risk factors, predict sleep and circadian-related susceptibility to disease, and provide the validated assessments of therapeutic efficacy. </p>

<p>Analyses of physiological and pathological readouts indicate the close interrelationship between physical and mental health and sleep and circadian function. Existing computational technologies are designed to probe these readouts systematically for indicators of sleep or circadian function and promising biomarkers of mood disorders and emotional dysregulation. These efforts will require multiomic data resources, which include daily patterns of metabolic profiles, epigenomics, and protein and RNA expression patterns. Advances in collection and accessibility of these data could permit development of sleep and circadian biomarkers that might improve evaluation and treatment of sleep-related risk and health outcomes across the lifespan.</p>

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<h2 class="field--name-field-component-section-titl component-section-section-title">CO2: Elucidate the significance of sleep and circadian biology to immune function and the microbiome.</h2>

            <div class="field field--name-field-component-section-desc field--type-text-long field--label-hidden clearfix field__item"><p><img alt="Decorative. Female scientist looking at test tube" data-entity-type="file" data-entity-uuid="d573dccd-49d8-44b7-82c0-cf324f3b3ca5" data-image-style="" height="256" width="384" class="align-left b-lazy" data-src="/sites/default/files/inline-images/shutterstock_159457628_resize_0.jpg" src="/modules/custom/nhlbi_blazy/images/clear.png" />Inflammatory homeostasis and the immunological response to damaged or unhealthy cells are closely coupled to preservation of sleep and circadian rhythms that sustain cellular physiology. The number of immune cells, such as lymphocytes and antigen presenting cells, and the expression of cytokines increase to maximal values during sleep and decrease during wakefulness. Because this homeostasis cannot be maintained during disturbances in sleep and circadian function, an array of abnormalities in innate and adaptive immunity may arise. Resilience to infection gets reduced, damaged, or unhealthy cells fail to be removed, and inflammatory equilibrium becomes disrupted. Sleep and immunity are also bidirectionally linked: the release of inflammatory factors promotes deep slow-wave sleep, which is critical to optimal host defense.</p>

<p>Scientists can now map circadian rhythms in previously unimaginable detail due to technological advancements in the 24-hour measurement of gene activity and proteomics in the microbiome. Understanding these multi system interactions in normal biological processes would allow us to define health and measure its perturbation by the environment, pathogens, or early disease processes more clearly. The ability to detect and prevent abnormalities associated with early disease processes could accelerate the development of new therapies and strategies for health promotion and resilience.</p>
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<h2 class="field--name-field-component-section-titl component-section-section-title">CO3: Elucidate the relationships between sleep and circadian rhythms and dementia pathobiology and clinical outcomes, including Alzheimer’s disease and related dementias.</h2>

            <div class="field field--name-field-component-section-desc field--type-text-long field--label-hidden clearfix field__item"><p><img alt="Decorative. Middle aged asian man with elderly father" data-entity-type="file" data-entity-uuid="1effbac3-46e3-4657-9c3b-efe717299333" data-image-style="" height="201" width="301" class="align-left b-lazy" data-src="/sites/default/files/inline-images/shutterstock_797625322_resize_0.jpg" src="/modules/custom/nhlbi_blazy/images/clear.png" />Changes in sleep and circadian rhythms typically occur with aging; however, there are distinct differences between the changes that occur in healthy aging and those associated with neurodegenerative diseases. Over the past decade, seminal findings linking sleep and circadian biology with neurodegeneration have offered compelling evidence underscoring the importance of sufficient sleep for optimal brain health. The discovery of the role of the glymphatic system in clearing accumulated neurotoxic waste products from the brain during sleep, and the strong association between sleep deficiency, sleep disorders and the vasculature, are key examples that not only highlight a new role for sleep in maintaining brain health at the individual level, but also demonstrate the impact of sleep and circadian sciences at the population and societal levels. Neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, and traumatic brain injury are all associated with disrupted sleep and circadian rhythms. More importantly, evidence of the bidirectionality of this relationship is mounting.  Not only do these conditions impact sleep, but sleep-wake and circadian disruptions can also exacerbate neurodegenerative pathologies.</p>
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<h2 class="field--name-field-component-section-titl component-section-section-title">CO4: Identify the neurobiological mechanisms underlying the perception of sleep quality, sleepiness, and fatigue.</h2>

            <div class="field field--name-field-component-section-desc field--type-text-long field--label-hidden clearfix field__item"><p><img alt="Decorative, african american male looking sleepy, yawning in front of laptop" data-entity-type="file" data-entity-uuid="b067c9e7-bed4-40e1-a701-749088432c87" data-image-style="" height="269" width="403" class="align-left b-lazy" data-src="/sites/default/files/inline-images/shutterstock_735692419_resize_0.jpg" src="/modules/custom/nhlbi_blazy/images/clear.png" />Improved understanding of the neurobiological mechanisms underlying sensations of sleepiness and fatigue, or the urge to sleep, could be transformative not only for sleep and circadian sciences, but for other fields. Emerging technologies permitting more precise brain and molecular imaging, combined with the recognition of the public health impact of widespread and chronic sleep loss, sleepiness, and fatigue, may offer new solutions to an unyielding challenge. fMRI studies indicate that sleep and circadian rhythms modulate the activity of brain regions underlying emotional regulation, cognitive function, coping, and interoceptive perception of pain and fatigue. For example, the study of interoception, which refers to the representation of the internal world, and includes the processes by which an organism senses, interprets, integrates, and regulates internal signals, is extremely relevant to sleep and fatigue. Both sleep and interoception are tightly connected to physical and mental well-being, with complex, dynamic relations between sleep and sensory processes within each modality of interoception (e.g., thermoception, nociception, visceral sensations, and subjective feelings about these sensations). A better understanding of these interrelations may facilitate management of chronic pain, insomnia, and other sleep and mental disorders. Additionally, identifying the similarities and differences in the underlying causes of fatigue as a symptom in many different disease conditions, and the role of sleep and circadian mechanisms in these conditions, is also of great importance. Psychological mechanisms and cultural factors also influence perception, and exploration of their impact on sleep quality, sleepiness, and fatigue are equally important and should be considered.</p>
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<h2 class="field--name-field-component-section-titl component-section-section-title">CO5: Develop chronotherapeutic approaches to prevent and treat chronic diseases.</h2>

            <div class="field field--name-field-component-section-desc field--type-text-long field--label-hidden clearfix field__item"><p><img alt="elderly man looking at his watch in front of pills and medicine bottles" data-entity-type="file" data-entity-uuid="8a331644-e9db-4aa4-88ef-7a08184855b5" data-image-style="" height="209" width="314" class="align-left b-lazy" data-src="/sites/default/files/inline-images/shutterstock_710055913_resize.jpg" src="/modules/custom/nhlbi_blazy/images/clear.png" /><span><span><span>The broad influences of natural, physiological rhythms on human cellular, molecular, and emergent systems suggests that further understanding of these rhythms might be leveraged to treat chronic conditions, including obesity, cardiovascular disease, metabolic and respiratory diseases, cancer, rheumatoid arthritis, and mental health disorders. Applying the insights gained to develop or refine chronotherapeutic approaches, such as adjusting the timing of treatments to circadian rhythms, could enhance their efficacy. </span></span></span><span lang="EN" xml:lang="EN" xml:lang="EN"><span><span>Research has shown that medical treatments for conditions such as asthma, hypertension, cancer, and cardiovascular disease work best depending on the time of day they are administered. For example, </span></span></span><span><span><span>better drug effectiveness for central nervous system disorders may be determined by considering how circadian regulation of the blood-brain barrier influences its permeability</span></span></span><span lang="EN" xml:lang="EN" xml:lang="EN"><span><span>.</span></span></span> <span lang="EN" xml:lang="EN" xml:lang="EN"><span><span>Additionally, correcting disturbed circadian rhythms, such as by advancing phase delays with the use of sleep restriction and light therapy, can be an important component in the treatment of some mental disorders, including seasonal affective disorder and peripartum depression. </span></span></span><span><span><span>Optimizing the timing of medication administration in accordance with circadian rhythm profiles could maximize efficacy and minimize toxicity or side effects. Such consideration may create paradigm shifting approaches to prevent or treat major medical conditions.</span></span></span></p></div>
      
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<h2 class="field--name-field-component-section-titl component-section-section-title">CO6: Develop tools and/or methods for the early prediction, detection, and treatment of sleep deficiency and sleep and circadian disorders in children and adolescents to promote lifelong health and wellbeing and prevent disease.</h2>

            <div class="field field--name-field-component-section-desc field--type-text-long field--label-hidden clearfix field__item"><p><img alt="African american female pediatrician hold stethoscope to examine small child, accompanied by his mother" data-entity-type="file" data-entity-uuid="35164d92-4953-43f8-8c76-e5d8ab6b764a" data-image-style="" height="285" width="427" class="align-left b-lazy" data-src="/sites/default/files/inline-images/shutterstock_1945636510_resize.jpg" src="/modules/custom/nhlbi_blazy/images/clear.png" />Sleep is critical to pediatric and adolescent development and daily functioning and impacts performance and health trajectories. The effects of insufficient sleep in children may persist into adulthood, and this has wide-ranging implications for health and life outcomes. Recent findings suggesting that epigenetic and metabolic effects of sleep deficiency and circadian abnormalities may be persistent and enduring across the lifespan provides a mechanistic basis. Additionally, maternal sleep deficiency has been linked to increased adiposity in offspring, and alterations in postnatal neurodevelopment, emotional regulation, and metabolic and cardiac risks have been associated with childhood sleep deficiency. Sleep deficiency and untreated sleep disorders can cause increases in blood pressure, atherosclerotic inflammation, and cardiometabolic disease risks at all ages.</p>

<p>Studies have also linked housing and neighborhood conditions to sleep loss. Sleep is particularly reduced in low-income and developmentally delayed children ages 3 to 6, and thus contributes to known health disparities that have long-term consequences. Evidence is emerging that environmental factors at the household and neighborhood level can also alter children’s sleep. Social vulnerability, the negative effects of external stressors on health at the community level, and adverse childhood experiences, which are stressful or traumatic life events that occur during the first 18 years of life, both have been linked to sleep disturbance in adults. Investigating the impact of sleep and circadian disruption early in life, and how these exposures affect disease and health trajectory across the lifespan, could help to identify opportunities for early interventions to prevent disease.</p>
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<h2 class="field--name-field-component-section-titl component-section-section-title">CO7: Standardize measurements and data and demonstrate how dissemination and implementation of high-quality care for sleep and circadian disorders can be improved by data science approaches in adaptive healthcare systems.</h2>

            <div class="field field--name-field-component-section-desc field--type-text-long field--label-hidden clearfix field__item"><p><img alt="3D illustration of DNA strand with binary code in the background" data-entity-type="file" data-entity-uuid="9798a5b3-c3c7-4e94-a029-999457cfb416" data-image-style="" height="214" width="342" class="align-left b-lazy" data-src="/sites/default/files/inline-images/shutterstock_1884429163_resize.jpg" src="/modules/custom/nhlbi_blazy/images/clear.png" /><span><span><span><span>The application of artificial intelligence (AI) is becoming increasingly common in the healthcare setting. Leveraging analytic approaches for big data by incorporating complex information from multiple sources – electronic health records cohorts, clinical research studies, registries, smartphones, and wearable devices, for example – could be used to advance our understanding of sleep and circadian disorders. But importantly, these approaches could also provide information about prevalence of these disorders, assist in the personalization of treatments, improve the allocation of resources, and inform healthcare policies. AI approaches could also be used to better understand sources of inequity in health care and health research related to sleep and circadian disorders. However, a major challenge is the lack of representation of diverse populations in big datasets. As innovation is not typically done through a health equity lens, it will be critical for research communities to consider this perspective in any approach that is developed. Recognizing the importance of information management and data sharing practices in publicly funded research projects, the NIH has announced more expansive policies aimed at improving transparency, reproducibility, and availability of scientific data.  </span></span></span></span></p></div>
      
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<h2 class="field--name-field-component-section-titl component-section-section-title">CO8: Embed omics-based approaches in real-world healthcare settings to facilitate personalizing treatments and cures for sleep and circadian rhythm disorders.</h2>

            <div class="field field--name-field-component-section-desc field--type-text-long field--label-hidden clearfix field__item"><p><img alt="Young African american male laboratory technician using a computer working in the lab" data-entity-type="file" data-entity-uuid="a2805ba9-f70a-4cf2-a42e-c157ecd326e1" data-image-style="" height="211" width="317" class="align-left b-lazy" data-src="/sites/default/files/inline-images/shutterstock_566980555_resize.jpg" src="/modules/custom/nhlbi_blazy/images/clear.png" />Personalized medicine and its challenging mission of harnessing patient-level data to refine (or personalize) care from diagnosis and treatment to monitoring, remains a prominent goal in medical research. One pathway to personalizing medicine is through an omics-based approach – that is, leveraging the various methods and tools used to investigate the structures, functions, activities, and interactions of different molecules within an organism.</p>

<p>Technological breakthroughs have been achieved by combining multiple “omics” approaches and artificial intelligence platforms and have revealed intriguing possibilities. Pragmatic research approaches within adaptive healthcare systems that continually improve care through daily learning and evaluation could transform healthcare delivery – not only within sleep and circadian medicine, but also in other medical fields. Furthermore, including the collection and timestamping of biological samples during normal clinical workflows could create the foundational infrastructure for precision medicine in sleep and circadian sciences.</p>
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<h2 class="field--name-field-component-section-titl component-section-section-title">CO9: Identify people-driven approaches to improve awareness of sleep and circadian rhythms and promote healthy sleep behaviors for the benefit of public health and safety.</h2>

            <div class="field field--name-field-component-section-desc field--type-text-long field--label-hidden clearfix field__item"><p><img alt="young african american woman speaking to a group of diverse young people" data-entity-type="file" data-entity-uuid="846078c2-d83f-4c27-9d8e-ee41dcfe5bdb" data-image-style="" height="252" width="378" class="align-left b-lazy" data-src="/sites/default/files/inline-images/shutterstock_1860453910_resize.jpg" src="/modules/custom/nhlbi_blazy/images/clear.png" /><span><span><span>Placing people at the center of public health promotion is required to access not-well-reached populations for both primary and secondary prevention, treatment, and cures. This people-driven approach matters. The persistent barriers faced by under-represented minorities, rural populations, children, geriatric populations, individuals with disabilities, and other underserved groups, limit the ability of healthcare system-based approaches to improve public health. Sleep health disparities remain an important focus in efforts to promote health equity, and they can be effectively addressed through community- engaged and people-based approaches. Moreover, the sizable costs associated with delayed care during advanced disease could be shifted to a preventative disease model through people- or community-driven approaches. Innovative educational approaches, as well as messaging similar to that used by the </span></span></span><a href="https://covid19community.nih.gov/" rel="noreferrer"><span><span><span><span>NIH Community Engagement Alliance (CEAL)</span></span></span></span><span><span><span><span><span> Against COVID-19 Disparities</span></span></span></span></span></a><span><span><span>, may be effective strategies for transferring health information and scientific advances from sleep and circadian biology researchers and healthcare providers to educators from diverse disciplines and underserved populations. Employing cognitive modeling approaches may also be considered when developing strategies that are people-driven. </span></span></span></p></div>
      
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