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 2: Reduce Human Disease

Using "omics" for therapeutic targets

How do we identify potential targets for therapy in the age of systems biology/genomics?

Submitted by (@nhlbiforumadministrator)

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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

Systems approaches to understand the pathogenesis of cardiovascular diseases, combined with in vivo validation

Critical Challenge

Submitted by (@yong.zhao)

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Strategic Goal: Goal 1: Promote Human Health

Computational biology modeling approaches

There is a need to develop computational biology modeling approaches to study normal variation in heart, lung, blood, and sleep (HLBS) systems.

Submitted by (@nhlbiforumadministrator)

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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

Redox regulation of cardiovascular and lung disease through thiols

Redox imbalance as represented by alterations in oxidative versus reductive stresses are well appreciated to occur during nearly all forms of cardiovascular and lung diseases. However, specific molecular mechanisms responsible for these changes remain largely unknown and poorly organized. Study of redox biology principals has revealed that protein cysteine thiols are a unique target for redox posttranslational modifications ...more »

Submitted by (@ckevil)

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Protein cysteine thiols are recognized to be important for multiple signaling and cell biology functions due to unique properties of oxidation/reduction resulting in a 'thiol switch'. However, oxidative modifications of thiols are highly complex involving nitrosation, sulfhydration, sulfenylation, and glutathiolyation among many others. It has become increasingly clear that these posttranslational modifications are associated with cardiovascular and pulmonary pathophysiology. Yet, many important questions remain such as: how these thiol modifications occur during disease and differ from health? How do these thiol switches impact protein function involved in cellular pathophysiology? And can thiol switch manipulation be exploited for therapeutic purposes to maintain cellular and organ health or treat disease? In order to begin to answer these questions, careful and comprehensive investigations are required to understand thiol-switching principals employing a host of molecular, biochemical and pathophysiological approaches.

Feasibility and challenges of addressing this CQ or CC :

Given the significant advances in quantitative analytical chemical and molecular techniques, molecular redox mediators and pathways, non-invasive imagine modalities and comprehensive translational study designs; multiple fields are uniquely poised that could provide significant insight into this critical challenge. Primary objectives would be to establish consensus analytical methodologies, chemical and molecular biology approaches, and cellular and animal models in conjunction with rigorous clinical investigations. Results from efforts at understanding the importance of ‘thiol switches’ will make significant clinical impact on cardiovascular and lung pathogenesis and would feasibly be accomplished in 5-10 years.

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Strategic Goal: Goal 1: Promote Human Health

Cardiac Engineering – Deciphering the Cardiome

To maintain cardiac health and prevent disease, there is a need to decipher the cardiome of cells and genes and use this knowledge (1) to better understand cardiac structure and function and (2) to engineer systems on the level of organs, organ systems, and the entire individual.

Submitted by (@nhlbiforumadministrator1)

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Improved CV health

Feasibility and challenges of addressing this CQ or CC :

new advances in study of the cardiome

Advances in in the sub-micro-world over the past several years have led to greater opportunities to better understand cells and genes. These new developments have and will continue to provide greater insight into understanding cardiac structure and function, which has and will likely to result in improved therapies for heart disease. The advances being made in science and technology have expanded the frontiers of cardiology as a result of important advances in micro-imagining and molecular diagnostic methods. These advances have transformed classical study of the macro-world of living human beings and the cardiac disease that afflict them.

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

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Strategic Goal: Goal 3: Advance Translational Research

Human Heart Systems Biology

In the human failing heart, it is the systems biology that ultimately fails: electrical, mechanical, and chemical perturbations in their function do not manifest in isolation, but critically impact on each other in health and disease. Investigation of human myocardium, unlike inbred rodent models, is challenging since no two humans are identical. There is a need for the collection and assessment of clinical patient data, ...more »

Submitted by (@janssen.10)

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Procured/stored tissue from these hearts could be made available NHLBI/NIH-wide, and studied by a large number of investigators on protein levels, RNA/DNA level, and/or histological assessments. This data could then be correlated to any other parameter assessed on these hearts, providing correlative guidance, through systems biology/neural network programming, for future mechanistic studies. For each additional parameter investigated, the number of correlation analysis (with any and all parameters, including clinical and biometric parameters) would mathematically double.

Feasibility and challenges of addressing this CQ or CC :

Supporting the basic collection of these in vivo and in vitro parameters and possibly the logistics for tissue distribution to collect correlative mechanical, proteomics, genomics, and histology data for correlation with the in vivo and in vitro data would allow for an NIH/NHLBI-wide translational approach to human heart failure that could encompass everyone’s “favorite” molecule, protein, pathway, and disease etiology. A logistical challenge is that such a project would likely exceed the funding of a single standard grant, but more importantly would surely exceed the standard 4-5 year duration, requiring long-term vision, planning, and buy in from NIH/NHBLI and investigators.

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

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Strategic Goal: Goal 1: Promote Human Health

Use of Evolutioinary Biology in Medicine

Given that chronic diseases are 'Evolutionary Biology' in reverse, can we use developmental and phylogenetic principles to diagnose and treat them safely and effectively?

Submitted by (@johntorday)

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

Details on the impact of addressing this CQ or CC :

Biomedical research is currently in crisis. Both basic science and translational science are failing to provide new insights to the causes of disease and their eradication. Instead, we are encouraged as biomedical researchers to devise ways of eliminating the symptoms of disease. This is a very bad practice since it facilitates the retention of maladaptive genes in the gene pool.

 

This practice is the result of continuing to practice biology and medicine descriptively, like Chemistry and Physics were as Alchemy and Astrology. The lack of a fundamental understanding of the First Principles of Biology originating in unicellular organisms fosters continued study of associations and correlations instead of causal mechanisms. If the National Science Foundation were still funding Astrology, we would see the same lack of predictive value that we see in biology and medicine today. Society cannot afford to continue sponsoring such pseudoscience. This problem is already recognized indirectly due to the failure of the Human Genome Project to fulfill its promise of curing common chronic diseases such as heart attack, stroke, diabetes and obesity. But the withholding of funding from the NIH to shake out the dead wood will not solve the problem, because it is due to the use of the wrong paradigm. Understanding how and why vertebrates evolved on the cellular-molecular level offers a way of understanding causation in biology and medicine rendering them predictive.

Feasibility and challenges of addressing this CQ or CC :

This initiative is highly feasible since we already have the methods available to us in the biomedical research community. The problem is in recognizing that applying 'omics' to the problems we face using same old same old Pathophysiology will not solve the problems of medicine. That precept is founded on Health as the absence of disease, which proved useful for a century, but we are now attempting to tackle more difficult fundamental problems that require a more powerful approach. The Evolutionary Biology approach offers the opportunity to define Health objectively rather than relativistically, i.e. health and disease are a continuum generated by the mechanisms of evolution.

Name of idea submitter and other team members who worked on this idea : John Torday, Virender Rehan, Neil Blackstone

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Strategic Goal: Goal 4: Develop Workforce and Resources

Establishment of an independent study section on Pulmonary Vascular Biology and Translational Research

The research on pulmonary vascular biology including smooth muscle cell biology and endothelial cell biology and related pulmonary vascular diseases such as pulmonary hypertension and related right heart failure, and endothelial dysfunction in lung vascular inflammation and acute lung injury, as well as pulmonary embolism and lung transplantation has been rapidly expanding. The field is attracting an ever increasing ...more »

Submitted by (@yyzhao)

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Establishment of a study section on Pulmonary Vascular Biology and Translational Research will provide adequate funding to stimulate innovative research on this rapidly expanding field and promote translational research and thereby promote human health by providing potential novel therapeutic strategies for the devastating diseases such as pulmonary hypertension and acute lung injury.

Name of idea submitter and other team members who worked on this idea : Youyang Zhao, Kurt Denmark, Asrar B. Malik, Mark Gladwin, Jahar Bhattacharya, Michael Matthay, Sharon Rounds, Jason Yuan

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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)

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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Strategic Goal: Goal 2: Reduce Human Disease

Novel methods to diagnose and treat microvascular ischemia

Microvascular ischemia is common, particularly in the setting of critical illness. We need better ways to evaluate, diagnose and treat these conditions, whether they relate to microvascular myocardial ischemia, as a primary diagnosis of complication of other acute illness, or non-myocardial ischemia during the course of surgery, injury, infection or acute illness.

Submitted by (@greg.martin)

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Details on the impact of addressing this CQ or CC :

Development of effective diagnostics would lead to improved treatments for myocardial and non-myocardial microvascular ischemia, and also advance understanding to extend the advance beyond this setting.

Name of idea submitter and other team members who worked on this idea : Society of Critical Care Medicine Executive Committee/Council

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Strategic Goal: Goal 2: Reduce Human Disease

Vascular biology and the pathophysiology of sepsis

Unravel the cellular & molecular mechanisms related to the vascular biology of sepsis and related cardiovascular collapse. The goal is to develop a new scientific framework for the prevention of sepsis related morbidity and mortality by applying novel approaches to discover new targets for biomarkers and therapy by promoting multidisciplinary research required for scientific cross-talk between complementary research disciplines ...more »

Submitted by (@greg.martin)

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Name of idea submitter and other team members who worked on this idea : Society of Critical Care Medicine Executive Committee/Council

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