Strategic Goal: Goal 2: Reduce Human Disease

Circadian strategies to improve therapies

What circadian-based strategies (e.g. timing of medication) can be applied to improve the efficacy of treatments for heart, lung, and blood diseases (e.g. hypertension, nocturnal asthma, thrombosis, obesity/diabetes)?

Submitted by (@nhlbiforumadministrator1)

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Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Strategic Goal: Goal 2: Reduce Human Disease

DEVELOPMENT OF A PERSONALIZED APPROACH TO SLEEP AND CIRCADIAN DISORDERS

There is developing evidence of major individual differences in pathways to different common sleep disorders such as obstructive sleep apnea. Moreover, there is evidence of different clinical presentations of disease and different outcomes. For example, some subjects with obstructive sleep apnea who get excessive sleepiness while others do not. The latter are still at risk for other consequences of the disorder such ...more »

Submitted by (@jnoel0)

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There is a strong rationale for application of a personalized approach to sleep disorders. This requires approaching this question using multiple domains as in other areas of medicine—clinical features, physiological factors, application of the –omic approaches, genetics. The impact of this will be several:

 

a. A new way to classify sleep disorders.

b. Identification of subgroups of patients with apparently the same disorder who will have different outcomes of therapy.

c. Identification of subgroups of patients who will have different approaches to diagnosis.

d. Identification of subgroups of patients with apparently the same disorder who will have different therapeutic approaches.

Feasibility and challenges of addressing this CQ or CC :

These sleep and circadian disorders are extremely common. There is a risk infrastructure for this type of research based on the large number of accredited sleep centers in the United States that could be used for subject recruitment and who can adopt similar techniques. There is also a rich set of data obtained from sleep studies that could be used to identify new patterns that reflect different subgroups of subjects. These studies need to be based on clinical populations of patients who present with the different disorders rather than on population-based cohorts.

Name of idea submitter and other team members who worked on this idea : Sleep Research Society

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Strategic Goal: Goal 1: Promote Human Health

Circadian-coupled rhythms in lung health

Does the homeostasis and health of the lung depend on circadian-coupled genomic function?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

The circadian genome is a highly conserved system producing 24-hr rhythms in gene expression in the lung. Uncovering the molecular/cellular pathways under circadian control and their significance would provide a new generation of mechanistic understanding of lung health and development.

Feasibility and challenges of addressing this CQ or CC :

Delineating circadian mechanisms of lung function would enable new strategies to phenotype, diagnose, and mange lung disease to be developed and tested.

Over the past decade, new discovery has uncovered a mechanistic interface between the circadian clock and fundamental cellular processes including oxidative stress, cell metabolism, immune and inflammatory responses, epigenetic modification, hypoxia/hyperoxia response pathways, endoplasmic reticular stress, autophagy, and regulation of the stem cell environment. While each of these processes is involved in lung function, the significance of circadian regulation in the development and maintenance of lung health is not well-understood.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Strategic Goal: Goal 2: Reduce Human Disease

UNDERSTANDING SLEEP AND CIRCADIAN DISORDERS AT A BASIC MECHANISTIC LEVEL

We need to understand sleep and circadian disorders at a more mechanistic level. This applies to both the pathogenesis of these disorders and to their impact on health. New neurobiological and molecular tools facilitate this research. The focus needs to be not only in brain but also the impact of these disorders on future of peripheral organs. The elucidation of the fundamental functions of sleep and the impact of ...more »

Submitted by (@jnoel0)

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Much of the research on the consequences of sleep/circadian disorders has focused on their consequences or behavior. This type of research needs to be continued and there are new opportunities in this area. These behavioral studies need to be established in model systems to parallel studies in humans. In addition, new neurobiological approaches, including optogenetics and use of DREAD, provide new tools for this investigation. Moreover, we now have powerful molecular tools to evaluate effects of sleep/circadian disorders both in humans and animal models. These include microarrays, RNA seq, etc. Moreover, genetic studies, e.g., in restless legs syndrome, have identified gene variants conferring risk for the disorder. We do not know, however, how these particular genes are involved in the pathogenesis of the disorder or whether they represent potentially targets for drug intervention. There is a need for studies both in animal models and in humans to elucidate the function of these genes. Studies in other areas are obtaining stem cells from biopsies in patients and then turning these into relevant target cells such as neurons to elucidate gene function using in vitro approaches.

The impact of this effort will be the following:

 

a. Taking our understanding of pathogenesis of sleep and circadian disorders to a new level.

b. Understanding the consequences of sleep and circadian disorders on different end organs at a more in-depth molecular level.

Feasibility and challenges of addressing this CQ or CC :

The sleep and circadian field have access to all the major cells systems for these studies—C. elegans, aplysia, Drosophila, zebra-fish, mice, etc. Moreover, there are already gene variants identified in human studies which require follow-up functional studies. The field has the expertise in all of the techniques described above. Moreover, there are more validated animal models for many of the common sleep disorders. Thus, this new approach is very feasible. 

Name of idea submitter and other team members who worked on this idea : Sleep Research Society

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Strategic Goal: Goal 1: Promote Human Health

Circadian Environmental Effects

Does circadian regulation modify the effects of environmental exposures (e.g., cigarette smoke, particulates, virus/bacteria, temperature, humidity, microbiome) on airway/lung remodeling and the intensity of associated epigenetic modifications?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Feasibility and challenges of addressing this CQ or CC :

An estimated >90% of histone modifiable sites on human chromatin are clock-coupled.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Strategic Goal: Goal 2: Reduce Human Disease

Circadian patterns of injury/repair pathways

What is the role of clock-dependent mechanisms in cell injury/repair pathways and tissue dysfunction in heart, lung, and blood pathophysiology? How are pathways involved in disease and repair affected by aging-dependent mechanisms?

Submitted by (@nhlbiforumadministrator1)

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Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Strategic Goal: Goal 1: Promote Human Health

INVESTIGATE DIFFERENTIAL VULNERABILITY TO SLEEP DEFICIENCY AND CIRCADIAN DISRUPTION

Studies in different subjects have shown that there are major individual differences in response to sleep loss and circadian disruption. Twin studies have shown that this is heritable. There needs to be an intensive effort to assess basis of these individual differences. This could include in-depth phenotyping studies, e.g., neuroimaging, genetic studies, “-omic” studies, epigenetic changes, etc.

Submitted by (@jnoel0)

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Details on the impact of addressing this CQ or CC :

There are major individual differences in response to sleep loss (both acute and chronic) and to circadian disruption. This has major impact both in terms of health consequences and in safety. Some individuals are particularly vulnerable to sleep loss and hence are more likely to have adverse consequences of losing sleep—increased risk of crashes, errors by physicians, etc. They are also more likely to be affected by metabolic and other consequences if they have chronic insufficient sleep.

 

Identifying the basis of these individual differences will have several impacts:

 

1. It will provide likely targets for development of biomarkers to assess effect of sleep loss and circadian disruption.

2. It will provide tools to risk stratify individuals and to employ preventative strategies to reduce risk of major adverse consequences.

3. It will identify novel pathways that could be the target for future intervention studies.

Feasibility and challenges of addressing this CQ or CC :

These studies are highly feasible. Phenotyping and recruitment strategies to study this question have been established in many laboratories. Moreover, more laboratories are utilizing genetic, -omic approaches and epigenetic approaches that could be applied to this question. There is also a developing repertoire of neuroimaging studies that can be applied to address this question.

Name of idea submitter and other team members who worked on this idea : Sleep Research Society

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Strategic Goal: Goal 3: Advance Translational Research

DEVELOPMENT OF BIOMARKERS FOR SLEEP INSUFFICIENCY, CIRCADIAN DISRUPTION AND SLEEP DISORDERS

There is an urgent need to develop quantifiable biomarkers for acute sleep loss, chronic sleep insufficiency, circadian disruption and sleep disorders such as obstructive sleep apnea. These problems are highly prevalent but currently we do not have biomarkers to use for case identification, prognosis, or assessing response to therapy. There are currently small studies that indicate the feasibility. A recent workshop ...more »

Submitted by (@jnoel0)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

The following will be the impact of addressing this critical challenge:

 

1. Having an assessment that can be used following a crash to assess the level of sleep loss of the driver.

2. Having a method to assess chronic sleep insufficiency as a potential pathogenetic process in patients with cardiovascular disease, hypertension, etc.

3. Having a method to estimate circadian phase so that in patients with chronic insomnia one can identify individuals with delayed sleep phase.

4. Having a technique to establish magnitude of circadian disruption to assess its role in pathogenesis of diseases such as cardiovascular disease.

5. Add a molecular biomarker to other techniques to screen for obstructive sleep apnea in high risk populations such as obese commercial drivers.

6. Utilize a biomarker signature to identify who with obstructive sleep apnea will be particularly at risk for downstream consequences such as cardiovascular disease.

7. Develop the equivalent of HbA1C to assess therapeutic response to CPAP

Feasibility and challenges of addressing this CQ or CC :

The first challenge is to identify a signature for each of these use cases. This will require initial studies in a small number of well phenotyped subjects with all the “-omic” techniques. Thereafter, these multiple cohorts, already available with blood samples, etc. and relative phenotype can be used for validation purposes.

Name of idea submitter and other team members who worked on this idea : Sleep Research Society

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Strategic Goal: Goal 4: Develop Workforce and Resources

NOVEL APPROACHES TO TRAINING IN SLEEP AND CIRCADIAN RESEARCH

Sleep and circadian disorders are relatively new areas of medicine. Most universities currently lack a critical mass of investigators to develop institutional T32 grants. Thus, there are, unfortunately, few such programs nationally. The Sleep Research Society has recognized this and is taking active steps to facilitate development of other T32 institutional training grants. This will not, however, help the majority ...more »

Submitted by (@jnoel0)

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Details on the impact of addressing this CQ or CC :

The current status of research training in sleep and circadian disorders suggest that new approaches are needed. The field has developed one multi-center training grant to bring training to different institutions. This is focused on genetic/genomic approaches. It is run by the University of Pennsylvania which has a well developed program in this area. The fellows in training are, however, at other institutions, i.e., Johns Hopkins, University of Michigan and Stanford. Web-based approaches are used for work-in-progress seminars, grant development workshops and group mentorship, and didactic lectures. This strategy could be used more broadly to develop research training in other areas of sleep and circadian research. Stimulating this would have a major impact on research training in this new field of medicine.

 

Another relevant strategy would be to encourage adding slots in a competitive way for sleep/circadian research to other existing institutional T32 grants.

 

There are multiple mechanisms in place to communicate opportunities to the sleep/circadian academic community, i.e., Sleep-L, administered by the National Center for Sleep Disorders Research; Sleep Research Society biweekly blog; the Sleep Research Network. Specific encouragement of this approach would broaden the base for research training and would be of high impact.

Feasibility and challenges of addressing this CQ or CC :

The field of sleep and circadian research has had a long commitment to facilitating research training. The Sleep Research Society has hosted Trainee Day at our annual meeting for 20 years. The Sleep Research Society is funding early-stage investigators through its Foundation. The American Academy of Sleep Medicine runs, in collaboration with the NHLBI, an event at NIH for early-stage investigators in clinical research. The American Academy of Sleep Medicine Foundation has a “Bridge to K Award” program that provides funds to early-stage investigators who just missed funding on their first application for a K award. The Sleep Research Society has provided travel funds for early-stage investigators to attend recent workshops held by different NIH Institutes including National Heart, Lung and Blood Institute. Thus, there is no doubt of the commitment of the field and its professional organizations.

 

The impact of these new initiatives would be to broaden the base for research training beyond a few institutions. The number of institutions with a critical mass of investigators to mount successful T32 institutional training grants is not sufficient to provide the necessary future biomedical research workforce in this area. Novel approaches, based on modern communication IT technology, are needed.

Name of idea submitter and other team members who worked on this idea : Sleep Research Society

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Strategic Goal: Goal 1: Promote Human Health

Health Disparities and Sleep

What is the role of health disparities in sleep and circadian health development?

Submitted by (@jcs500)

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Strategic Goal: Goal 1: Promote Human Health

Do our modern "traditional" sleep schedules defy nature?

Here's an interesting article which shows that the modern tradition of eight hours of unbroken sleep might actually be unnatural, and quite different from what our ancestors typically did: http://www.bbc.com/news/magazine-16964783 So, maybe the majority of our modern societies (even the people without recognized sleep disorders) are unwisely fighting against biology? Perhaps a lot of people's health issues, such as ...more »

Submitted by (@apollia112)

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See comments

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Name of idea submitter and other team members who worked on this idea : Apollia

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Strategic Goal: Goal 2: Reduce Human Disease

Elucidate the different causes of circadian disorders, and tailor the treatment to the cause

There are several possible physiological causes of Circadian Rhythm Sleep-Wake Disorders (CRSWDs), including lack of sensitivity to light, over-sensitivity to light, deficiencies in the ipRGC cells of the retina, lack of melatonin production, long elimination time of melatonin, long intrinsic circadian period, differences in timing of sleep relative to internal circadian rhythms, differences in tolerance to phase mismatch, ...more »

Submitted by (@peter0)

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By analogy, a patient may complain of abdominal pain. This could be due to infection, food poisoning, ulcers, gall bladder, cancer, etc. Imagine if we treated all these patients by removing their gall bladder. There would be some successes, and many failures. Surveys of the literature would be unable to conclude that there's a well established successful treatment. That's the state of treatment of CRSWDs today.

 

CRSWDs such as Delayed Sleep-Wake Phase Disorder and Non-24-Hour Sleep-Wake Disorder cause suffering and inability to work normal hours, and often result in otherwise productive individuals being unable to find jobs and having to seek disability support. Those who force themselves into a conventional schedule often end up with chronic health problems, resulting in further cost to themselves and to society.

Feasibility and challenges of addressing this CQ or CC :

A major challenge is to diagnose not only a CRSWD but also its underlying cause. Improved biomarkers are essential to this effort, and are the subject of other Questions/Challenges. So too are a better understanding of the effects of light and melatonin on patients with these disorders, with the differing underlying impairments studied separately. With improvements in genetic testing and analysis, and improved sensor technology and automated data analysis, we are at the threshold of being able to study these underlying causes of CRSWDs.

Name of idea submitter and other team members who worked on this idea : Peter Mansbach

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