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.

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. 

Treatment of human diseases

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

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

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.

This will provide an in silico computational platform to study human cardiac pathology. Note: by different horizontal levels, we mean for example measuring and modeling individual ion channels, transporters or myofilament properties in myocytes. By different vertical levels, we mean for example gogenomic/proteomic to cellular, and cellular to more integrative levels.

Advances in high-speed computation techniques and high-throughput measurement make the achievement of this challenge doable.
An integrated understanding of the eletromechanical activity of the human heart is needed to develop more effective approaches to cardiac disease diagnosis, treatment, and prevention. Robust computational models of human electromechanical activity that incorporate ion channel kinetics, calcium handling and dynamic changes in the intra-/extracellular milieu from human cardiac tissues are needed develop such an understanding and to provide an experimental platform to test interventions designed to maintain cardiac function. Computational models should be scalable and incorporate subcellular molecular mechanisms to whole system levels of integration to be most effective.

Defining earliest elements of disease and strategies for prevention

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?

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.

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.

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NIH has acknowledged that the lack of training in the field of lymphatic biology has impaired research progress in the area. Traditional methods that the NIH uses (T32) have not adequately addressed this issue as there are currently NO such programs in existence. One of the critical problems that must be overcome to advance the field is that few individual institutions in the US have a large enough body of lymphatic biology investigators to fit the classic training grant schemes. Overcoming this hurdle will significantly help advance research in the field. Consideration of other innovative approaches that utilize web-based or other methods to deliver distance education among local or regional institutions in this field should be investigated. Establishment of these innovative approaches would broaden the pool of investigators for research training and would significantly advance the field and thus be of high impact.

Research in the lymphatic biology field has historically lagged behind other vascular areas. However, interest in lymphatic biology and medicine has grown rapidly over the last decade. The Lymphatic Education & Research Network (formerly LRF) has had a long-standing commitment to developing research and training in lymphatic biology through its post-doctoral fellowship program, support for conferences/symposia and by providing travel funds for early-stage investigators to attend these meetings. Since very few places in the US have enough researchers trained and active in lymphatic biology, initiatives to broaden the base for research training would have to utilize novel approaches. Thus, the challenge will be to develop training programs that can address the needs of new lymphatic biologists at multiple institutions at geographically distributed sites. Approaches that use modern communication IT technology, and distance learning methods could deliver parts of the training. But innovative approaches to incorporate training beyond didactic learning need to be developed.

Advance discovery and treatment

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

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.

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.

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.