Goal 3: Advance Translational Research

Integrate mechanistic and translational research

Other entries have asked for support for translational research. To be successful, this must be integrated with mechanistic research. Ideally. MD-PhD teams would get together. Challenges in translation: find formulation, preclinical toxicology, phase I trials to establish safety, biomarkers. Challenges in mechanism: RNA-Seq, Chip-Seq of relevant cells, KO mice by Cas-CRISPR, deep expertise in the relevant discipline.

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

Details on the impact of addressing this CQ or CC

Translation alone is fishing in the dark, with low likelihood of success. Mechanistic alone is just science for the sake of science, because academic careers are promoted by high profile publications. The NHLBI can change this!

Feasibility and challenges of addressing this CQ or CC

The NHLBI can change this by giving dual awards to qualified teams. Basically and R01 for the mechanistic work ($ 250 K per year for 5 years) coupled with funding for translational research (probably $ 6 m for a typical program to reach phase I)

Name of idea submitter and other team members who worked on this idea Klaus Ley

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37 up votes
9 down votes
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Goal 2: Reduce Human Disease

Balancing Risks and Benefits: How Do Clinical Guidelines in Cardiovascular Medicine Promote the Health of an Individual?

Much of the hopes for precision medicine (as outlined Dr. Dr. Collins) are based on deriving large amounts of genomic, proteomic, epigenomic and metabolomic data on large cohorts of patients. It will take decades to build these cohorts and even more time to analyze them and derive specific conclusions on how these will help individualize treatments.

However, there is a pressing need for how to individualize contemporary... more »

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

Details on the impact of addressing this CQ or CC

Decisions on whether or not to place a patient with atrial fibrillation on chronic anticoagulation or on statin therapy are often based on guidelines and cardiovascular risk calculators.

Patients with a higher risk of stroke are more likely to receive anticoagulation and patients with a higher risk of a myocardial infarction are more likely to receive statin therapy.

However, these cardiovascular risk calculators do not really take into account the potential side effects and impact on the lifestyle of the patients.

Physicians will stop anticoagulation in a patient with atrial fibrillation if the patient has suffered a life-threatening bleed but there are no specific evidence-based guidelines as to how one should proceed if the bleeding is minor.

it is easy to compute the cardiovascular risk and overall mortality benefit of placing a patient on statins but how does one factor in the impact that statins have on the quality of life of an individual?

Developing novel evidence-based approaches to individualize therapies that factor in cardiovascular benefits as well as potential side effects and diminished quality of life could have a major impact on appropriately using treatments and reduce the arbitrariness of some medical decisions.

Name of idea submitter and other team members who worked on this idea Jalees Rehman

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1 net vote
1 up votes
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Goal 1: Promote Human Health

ESTABLISH NORMATIVE AGE- AND GENDER-SPECIFIC DATA FOR SLEEP DISRUPTION, SLEEP QUALITY AND CIRCADIAN TIMING

There is growing evidence that sleep durations are progressively declining in the United States. Moreover, sleep durations are different at different ages and in different ethnic groups. Currently definitions of normal are based on consensus since there is a lack of key data. Defining normal as with FEV1 is a critical step.

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

Details on the impact of addressing this CQ or CC

There is a developing evidence from both basic research and clinical research on the role of insufficient sleep in different co-morbidities. These include cardiovascular disease, hypertension and metabolic disorders. The Centers for Disease Control (CDC) has appreciated the importance of this that adequate sleep is one of the pillars of health. As part of the CDC-supported program on sleep health, a consensus statement has been issued on normal sleep duration. The group doing this on behalf of the American Academic of Sleep Medicine and Sleep Research Society realized that our evidence base is inadequate at this time. Thus, there is a need to focus on this critical challenge. Sleep duration varies across the lifespan and there is some evidence that it is different in different ethnic groups. Thus, there is a need for comprehensive efforts to address this question and to obtain normative data for sleep duration that is age-, gender-specific and with respect to different ethnic groups.

Feasibility and challenges of addressing this CQ or CC

There are now recent cohorts at NIH assessing sleep duration using not only self-report but also actigraphy. These could be used as an initial approach to address this question. This will require some degree of coordination between NIH Institutes. In the future a cohort that is specific to addressing questions about sleep duration and other sleep problems would be optimal. There are major prevalent public health issues. This would be facilitated by development of new mobile approaches to assessing these behaviors in an objective way.

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

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157 net votes
214 up votes
57 down votes
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Goal 3: Advance Translational Research

Cell-specific drug delivery

New paradigms are needed for developing both deliver systems AND drugs to achieve therapeutically effective cell-specific drug delivery.

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 proposed development is essentially needed for new effective therapies and personalized medicine.

Feasibility and challenges of addressing this CQ or CC

The proposed approach is feasible but requires that new paradigms are adopted by organizations and researchers.

Name of idea submitter and other team members who worked on this idea Karel Petrak

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19 net votes
22 up votes
3 down votes
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Goal 2: Reduce Human Disease

Non-obstructive Coronary Disease

It is increasingly apparent that ischemic heart disease does not equal obstructive coronary disease. There is a large, heterogeneous population of individuals who present to the ED with chest pain syndrome with or without a troponin elevation, who on diagnostic evaluation have non-obstructive disease and who on prospective studies have increased risk for ACS and early mortality; other literature shows the same for coronary... more »

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

Details on the impact of addressing this CQ or CC

Patients with non-obstructive coronary disease represent a large proportion of patients who report to the ED with chest pain of cardiac origin. This hetergeneous group of patients have elevated ACS/mortality risk, yet little is known of the underlying pathophysiology or of the precipitants of chest pain and events. Research focused on characterizing distinct patient groups and associated pathways by which environmental factors precipitate chest pain and events would provide enormous benefit in the development and targeting of interventions to improve patient outcomes and reduce risk of catastrophic cardiac events.

Feasibility and challenges of addressing this CQ or CC

The challenges include assembling a sufficiently large patient sample to characterize distinct phenotypes. The technologies for this characterization are sufficiently disseminated to accomplish this. Furthermore, the technologies for ascertaining key elements of pathophysiology - e.g., vascular, autonomic - are also widely available. The recent expansion of technologies for ecological measurement of environmental factors and of physiological phenomena make this a feasible undertaking at this time

Name of idea submitter and other team members who worked on this idea Matthew Burg, PhD

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34 net votes
52 up votes
18 down votes
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Goal 2: Reduce Human Disease

Gasotransmitter regulation of cardiovascular and lung health and disease

Gasotransmitters, such as nitric oxide, hydrogen sulfide, carbon monoxide, and hydrogen, have emerged as potent mediators of cardiovascular and lung cellular and molecular pathophysiology. While the physiological importance of these agents is becoming clearer, studies of gasotransmitters continue to suffer from several limitations such as formation, detection, metabolism, and molecular and cellular mechanistic insights.... more »

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

Details on the impact of addressing this CQ or CC

It is well known that gasotransmitters participate in numerous aspects of cardiopulmonary physiology and pathology. However, several limitations exist with regard to how and when changes in gasotransmitters may occur during disease versus health, and whether employing gasotransmitters in a therapeutic manner could alleviate pathology and/or maintain physiological homeostasis. Support of research addressing mechanisms of gasotransmitter formation and metabolism, clinical and experimental pathophysiological detection, and clinical and experimental therapeutic approaches will significantly advance the field along with understanding of multiple cardiopulmonary disease processes.

Feasibility and challenges of addressing this CQ or CC

Given the significant advances in quantitative analytical chemical and molecular techniques, molecular 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, (bio)chemical and molecular biology approaches, and cellular and animal models along with rigorous clinical investigations. Results from efforts at understanding the importance of gasotransmitters will make significant clinical impact on cardiovascular and pulmonary diseases that would feasibly be accomplished in 5-10 years.

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-5 net votes
6 up votes
11 down votes
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Goal 2: Reduce Human Disease

Vascular Origins of Cognitive Decline

A comprehensive research plan is needed to identify the vascular causes of cognitive decline, to develop early treatment options, and most ideally, develop effective measures to maintain cognitive function.

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

Details on the impact of addressing this CQ or CC

Reduction in the number of elderly with cognitive impairment would not only increase quality of life but would reduce health care costs. Research is indicating that the pathologic decline in cognitive function is complex and may involve multiple pathways of cardiovascular and metabolic origin.

Feasibility and challenges of addressing this CQ or CC

Addressing this issue requires research on vascular biology, tools for brain imaging and measurements of cognitive decline, all of which are advancing in development and implementation. The 2013 BRAIN Initiative includes $100 million in commitments from 5 federal agencies, including $46 million from NIH in grant awards focusing on new tools and techniques.
The frequently observed cognitive decline with aging can occur in a mild state or can progress to forms of dementia that are devastating to individuals and families and require a functioning and affordable support system for the affected individual. The vascular origin of this decline is only beginning to be understood. With increasing numbers of the US population surviving to their 80s and 90s, healthy cognition is critical for these elderly to be able to live independent functioning lives. .

As always commitment of funds is required as well as identifying appropriate research populations and efficient study designs.

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

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30 net votes
51 up votes
21 down votes
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Goal 2: Reduce Human Disease

Sublingual Immunotherapy for Treatment of Asthma

As the current chair of the Research and Training Division, I would like to convey that the AAAAI membership would like the NHLBI to consider the following in the development of its strategic plan: What role should sublingual immunotherapy play in the treatment of asthma?


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 Mitchell Grayson on behalf of the American Academy of Allergy, Asthma, and Immunology

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-9 net votes
5 up votes
14 down votes
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Goal 3: Advance Translational Research

Increased receptivity to probative programmatic trials

We believe there should be greater openness to large, simple trials that answer clear questions of interest (e.g. does giving children more fruits and vegetables while changing nothing else lead to weight loss?; does eating breakfast regularly lead to weight loss?; etc.). The conduct of such trials may sometimes be expensive but can sometimes be only modestly costly if they are kept simple. However, it is difficult to... more »

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

Details on the impact of addressing this CQ or CC

While we do not mean for a moment that we should drift away from mechanistic science, we believe that there should also be openness to addressing some questions that are simple and perhaps even slightly dull, but can be unequivocally answered with a trial. In this way, beliefs can be converted to facts.

Feasibility and challenges of addressing this CQ or CC

It is difficult to seek funding for such trials because reviewers want to see more testing of mechanisms, more physiologic outcomes, more testing of hypothesized mediating variables, and more exciting scientific hypothesis tests.

Name of idea submitter and other team members who worked on this idea David B. Allison, Ph.D.; Kevin Fontaine, Ph.D.; Kathryn A. Kaiser, Ph.D.; Andrew W. Brown, Ph.D.; Edward C. Archer, Ph.D.

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1 up votes
1 down votes
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Goal 2: Reduce Human Disease

Pulmonary Vascular Diseases

Does anticoagulation with warfarin improve outcomes (time to clinical worsening, qualtiy of life, exercise capacity) in patients with pulmonary arterial hypertension treated with current oral/inhaled therapies? There are substantial "unknowns" and practice variation in anticoagulation in PAH. Resource utilization is also a factor here. We may either be helping patients (or hurting them with side effects) by using anticoagulation.... more »

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

Details on the impact of addressing this CQ or CC

This is a view of problems in the field.
Pulmonary Hypertension Clinical Research: Current Problems and Possibilities
Current studies limited to the short term, with soft outcomes.
No mechanistic studies embedded in trials.
Control of phenotype is weak.
Small n: lumping of cohorts.
No factorial of advanced design.
No biological samples obtained for study.
Failure to study basic management issues.

Name of idea submitter and other team members who worked on this idea ATS Member

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2 net votes
2 up votes
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Goal 3: Advance Translational Research

Community Trials for Cardiovascular Health Enhancement

There is a need to initiate innovative community trials that are: theory-based; are integrated multi-component, multi-setting, and multi-level (i.e., they target individual, family, community, and built environment); engage community stakeholders; and use community-participatory research principles to enhance cardiovascular health (CVH) in vulnerable and diverse populations.

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

Details on the impact of addressing this CQ or CC

Global impact on cardiovascular health.

Feasibility and challenges of addressing this CQ or CC

There are smaller scale community interventions but none in the literature that focuses on larger-scale multi-level trials as proposed here. This CQ would target vulnerable and diverse populations to reduce health disparities.
NHLBI supported the stroke belt initiative, and the exemplars in community CV health research: (e.g., the Stanford 5 City Project, The Minnesota Heart Health Program, The Pawtucket Heart Health). The next generation of community CVH research should harness the lessons from these studies, findings for the 8 Americas (Chris Murray), and numerous results from NHLBI cohort studies to implement large-scale community trials for cardiovascular health enhancement.
Resources for a large scale study could be a challenge. Ability to motivate a whole community, to prevent contamination, and to sustain interventions would be a challenge.

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

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-1 net votes
9 up votes
10 down votes
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Goal 2: Reduce Human Disease

Cellular senescence and age-related lung disease?

What is the role of cellular senescence in age-related lung disease? Do environmental factors, including smoking, contribute to the pathogenesis of lung disease through their ability to induce premature senescence? Does the accumulation of senescent cells in distal organs contribute to age-related lung disease through systemic inflammation?

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 Ferruccio Galbiati

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-6 net votes
4 up votes
10 down votes
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