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)

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

Details on the impact of addressing this CQ or CC :

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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Goal 1: Promote Human Health

Human normal variation and resilience across lifespan

What is the measureable normal human variation at the -omic, cellular, organ, and system levels within the population and across the lifespan? • What are the range of normal human cellular functions that create resilience at all levels—cells, organs, organ systems? • What inter-organ, tissue, and cellular communications maintain individual health and the health of populations? • How do we understand why individuals with ...more »

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 :

• Will provide a better definition of what is normal in order to better interpret and exploit the big data available through increased personalized monitoring and use of EMRs.

• Insights into the underlying mechanisms of resilient phenotypes will provide new paradigms for disease prevention and treatment.

Feasibility and challenges of addressing this CQ or CC :

Feasibility will depend on the level of investment (large) and accessibility to commons data.

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

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Goal 2: Reduce Human Disease

How to maximize the opportunities and promise of emerging omics research? Develop scientific commons

In the late 20th century, the NHLBI cohorts were created as separate entities with specific research goals. The NHLBI’s funding of GWAS served as a powerful incentive for collaboration among the NHLBI-funded cohort studies. The creation of a scientific commons would provide a major national resource comprising the participants, their deeply phenotyped data, their biological samples, and the investigator expertise to ...more »

Submitted by (@psaty0)

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

Details on the impact of addressing this CQ or CC :

Advance discovery and treatment

Feasibility and challenges of addressing this CQ or CC :

Feasible with few challenges. The system would need infrastructure support.

Name of idea submitter and other team members who worked on this idea : Psaty & Tracy

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Goal 1: Promote Human Health

Host and environmental factors effect on transplantation biology and regenerative medicine

How does inflammation and cell injury induce the immune system during transplant rejection? How do we control immune responses to enable cell- and tissue-regenerative strategies? • How does inflammation and cell injury induce the immune system during transplant rejection? • How do we control immune responses to enable cell and tissue regenerative strategies? • How do we use iPS cell based and gene editing based therapies ...more »

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 :

Treatment of human diseases

Feasibility and challenges of addressing this CQ or CC :

Facilitated by progress in genome editing, stem cell biology, immunology

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

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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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Goal 2: Reduce Human Disease

National network to study the pathobiology of sepsis

Sepsis is the leading cause of death in hospitalized patients, the 3rd leading cause of death in all people in the US, the most common condition leading to widespread vascular collapse, among the most common causes of respiratory failure, and a frequent cause of acute cardiac dysfunction.

Submitted by (@greg.martin)

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

Details on the impact of addressing this CQ or CC :

Developing a national network to address important aspects of sepsis (causes and consequences of cardiac dysfunction, molecular determinants of respiratory failure) and serve as a trials group for testing novel interventions for new discoveries.

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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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)

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

Details on the impact of addressing this CQ or CC :

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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Goal 1: Promote Human Health

Intersecting Developmental Biology with Vascular Physiology and Biology

Although many think of the vasculature as a lump sum of vessels that all react in a similar fashion to a certain stimulus, e.g., alpha-adrenergic activation, this is not the situation. For example, coronary resistance vessels show little to no direct response to alpha-adrenergic activation while resistance vessels in most organs show marked constriction. Another example is the response of different vessels to angioplasty ...more »

Submitted by (@wchilian)

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

Details on the impact of addressing this CQ or CC :

A challenge facing many specialists in vascular medicine, vascular surgery, and cardiology is understanding the ramifications, and the basis, of the vascular pathology in the context of the organ system. Another way of re-stating this as a question is: Are the unique attributes of the vascular biology, pathology and physiology of a particular organ system connected to specific aspects of development. This question would help both the basic on clinical scientists understand the basis of why a blood vessel in the kidney may be different than one in the heart, or in the brain with the goal of devising more selective therapies to approach vascular disease in specific organs. Scientists in the area of vascular development have long appreciated that vascular cells in different organs arise from different embryological origins; yet how this information translates into the intricacies of vascular control, or responses to pathology is not resolved. Understanding the basic biological mechanisms of how the embryological source of the vasculature affects pathology and physiology could engender treatment of vascular disorders.

Feasibility and challenges of addressing this CQ or CC :

This idea could be implemented by encouraging multi-PI efforts from vascular developmental biologists, and investigators engaged in studies of microvascular control mechanisms and/or vascular biologists interested in vascular pathologies such as restenosis and vascular lesions. Advances in fate mapping techniques have enabled developmental biologists to track embryological origins of cells into specific organ systems into adulthood. With such a multi-faceted approach a better understanding of vascular physiology and pathophysiology will be obtained that hopefully will be translated into more effective treatments.

Name of idea submitter and other team members who worked on this idea : William M. Chilian

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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)

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 : Society of Critical Care Medicine Executive Committee/Council

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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)

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

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

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Goal 2: Reduce Human Disease

The effects of environmental factors on heart, lung, blood, sleep disease development across the lifespan

How do growth, development, exposure, and behavior affect heart, lung, blood, sleep disease development and outcome throughout the lifespan?

 

How do you improve organ function/capacity during childhood?

Submitted by (@nhlbiforumadministrator1)

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

Details on the impact of addressing this CQ or CC :

Defining earliest elements of disease and strategies for prevention

Feasibility and challenges of addressing this CQ or CC :

If we don’t start now, it will never get done

. Challenges:

• Determine if elements of cell aging, including stem cell aging and senescence, affect disease progression and the effectiveness of therapeutic interventions

• Can we develop iPS based or other cell based bioengineered tools to more precisely define cellular and molecular responses to particular exposures?

• How do we identify, prioritize and measure relevant environmental exposures?

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

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