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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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)

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 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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Goal 1: Promote Human Health

ELUCIDATING BASIC MECHANISMS OF SLEEP DEFICIENCY AND CIRCADIAN DISRUPTION ON HEALTH THROUGH THE LIFESPAN

There are developing data from clinical studies that sleep deficiency and circadian disruption have multiple adverse consequences for health. The clinical data provide the base for mechanistic studies. Studies in animal models indicate that both circadian disruption and insufficient sleep later gene expression in peripheral tissues. Moreover, the effect of sleep loss in molecular changes in brain changes with age. ...more »

Submitted by (@jnoel0)

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

Details on the impact of addressing this CQ or CC :

There is no doubt that insufficient sleep and circadian disruption are very common in our society. There are also compelling epidemiological data that they are associated with multiple adverse consequences, including increased cardiovascular disease, increase in metabolic abnormalities such as insulin resistance and for shift work an increased incidence of specific concern. Animal studies based on microarrays are showing that inadequate sleep and circadian rhythm alter gene expression not only in brain but also in peripheral tissues. These studies are hypothesis-generating and there are many opportunities for hypothesis-driven research in this area to assess mechanisms. Identifying mechanisms will allow investigators to begin to assess mechanisms of individual differences and to identify new pathways for intervention.

Feasibility and challenges of addressing this CQ or CC :

Sleep and circadian research is in a very strong position. Sleep and clock function has now been identified in all the major model systems—C. elegans, Aphysia, Drosophila, zebra-fish, mice, etc. Thus, there is a strong platform to assess conserved pathways for effect of sleep loss and circadian disruption. Moreover, microarray studies have identified likely pathways thereby setting up hypothesis-driven research. There are major opportunities in this area.

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

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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)

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

Details on the impact of addressing this CQ or CC :

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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Goal 2: Reduce Human Disease

Improve ineffective treatments for circadian rhythm disorders

I have extreme delayed sleep phase disorder (DSPD), a circadian rhythm disorder (CRD). I fall asleep at dawn and wake up early afternoon. My dim light melatonin onset (DLMO) is at 5:30 am. A normal person’s DLMO may be at 9 pm, for example. CRD treatment—prolonged bright light after temperature nadir, dark restriction/melatonin starting several hours before natural bedtime, darkness till temperature nadir—does not work ...more »

Submitted by (@susanpl)

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

Details on the impact of addressing this CQ or CC :

Circadian rhythm disorders (delayed sleep phase disorder, non-24-hour sleep-wake disorder, irregular sleep-wake disorder) have been ignored by many sleep researchers. They should not be. First, they reduce lives to rubble: education, employment, partnering, and parenting suffer or are not possible. Second, nocturnals who force themselves to live a diurnal life are at higher risk of disease (as are diurnals who work 3rd shift) and accidents. Third, evidence is mounting that circadian rhythms play a significant role in immunity, cancer, heart disease, diabetes, obesity, metabolic (dys)regulation, mental health, medication administration, and public health (think of the spike in accidents after spring and fall time changes).

Feasibility and challenges of addressing this CQ or CC :

To date, most circadian research has been conducted on "normals" who don't have CRDs. But their responses to light and dark cues differ from those of CRD patients. Please conduct circadian research on CRD patients--just as you would conduct diabetes research on diabetics.

 

Also needed: convenient ways to test for dim light melatonin onset, temperature nadir, and other circadian biomarkers. Right now, such tests are limited to study settings.

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

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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)

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

Details on the impact of addressing this CQ or CC :

See comments

Feasibility and challenges of addressing this CQ or CC :

See comments

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

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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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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)

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

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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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)

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

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

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Goal 1: Promote Human Health

ROLE OF HEALTH DISPARITIES IN SLEEP AND CIRCADIAN HEALTH—ENVIRONMENT

Self-report data indicate that insufficient sleep is more common in minority populations. This seems to be related to socioeconomic status. There is a need to move this beyond self-report and obtain objective measures in the relevant populations. Moreover, the basis of this difference needs to be established. What aspect of the environment leads to these differences, e.g., noise, stress related to sense of vulnerability, ...more »

Submitted by (@jnoel0)

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

Details on the impact of addressing this CQ or CC :

Self-report indicates that sleep duration is lower in minority populations. This seems to be related to socioeconomic groups. To address this issue requires understanding the basis of this and developing appropriate interventions.

 

The impact of this is as follows:

 

a. Implementing new technology based on mobile approaches to assess sleep duration in subjects in different socioeconomic groups.

b. Developing a comprehensive approach to understanding and evaluating environmental influences in sleep and circadian rhythm.

c. Designing and testing intervention to increase sleep duration in disadvantaged populations.

d. Improving the sleep health of minority populations.

Feasibility and challenges of addressing this CQ or CC :

There is rapidly developing new mobile technology to assess sleep duration and other phenotypes in individuals living in their normal lives. There are a number of studies currently being conducted that could be leveraged to address this question. There are also developing approaches to assess environmental influences on sleep and circadian rhythm such as noise, light exposure, etc. Thus, this question could be addressed in the near future.

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

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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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