Goal 4: Develop Workforce and Resources

Suipport new research using the R21 mechanism

The decision by NHLBI to not support the R21 mechanism may be stifling new and innovative research, partcularly by young investigators who do not have a track record of R01 funding. The critical challenge is to keep funding new ideas from younger investigators to keep their careers viable while they obtain the data and publications necessary for further R01-level funding.

Submitted by (@georgeporter)

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 state of NHLBI funding rates for R01s are so low that we are undoubtedly loosing many young researchers as the fail to obtain adequate support for their research. Funding R21 grants will allow new, innovative, and perhps risky projects to proceed, while keeping less established researchers in the field. Re-establishing R21 funding may prevent the impression that NHLBI is more interested in supporting established labs and not advocating for and supporting new investigators.

Feasibility and challenges of addressing this CQ or CC :

Given the limited budget of R21s, they will not have as large an impact on the overall budget of NHLBI as the equivalent number of funded R01 grants. Therefore, this change is feasible from a financial standpoint. Obviously, funding R21s will decrease funding for other mechanisms. Finally, it is possible that many of these grants will not lead to advances in the field, but it is my understanding that studies show the same thing about R01s.

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

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101 up votes
14 down votes
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Goal 1: Promote Human Health

Promoting health through simultaneous prevention of obesity and eating disorders

How to best promote healthy weight while also not stigmatizing obesity and creating risk for eating disorders (i.e., weight concern and body dissatisfaction) in youth. How to tackle both without contributing in unwitting way to development of either.

Submitted by (@tantillo)

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

Details on the impact of addressing this CQ or CC :

Studies show that diets do not lead to sustained health benefits for the majority of people and several studies indicate that dieting is actually a consistent predictor of future weight gain. Repeated cycles of losing and gaining weight are linked to heart disease, stroke, diabetes and altered immune function. Children and adolescents are especially vulnerable to the impact of dieting. Several long-term research studies show that girls and boys who use unhealthy weight control practices (including dieting) in early teen years are more likely to become overweight five years later, even if they started out at normal weight. These studies also show that early teen boys and girls who use unhealthy weight control practices are at greater risk for binge eating, use of severe weight control practices ( vomiting, diet pills, laxatives and water pills), and eating disorders compared with adolescents not using weight-control behaviors.

 

Since our culture tends to create weight bias and obesity stigmatization, it is not surprising to see our children become increasingly fearful of becoming “fat.” Weight concern can be experienced by underweight, average weight and overweight children and teens. Studies have shown that body dissatisfaction, especially weight concern (for early teen boys and girls), can lead to overweight, binge eating, severe weight control practices, and eating disorders. Weight teasing by family members and peers can also increase the risk for eating disorders.

Feasibility and challenges of addressing this CQ or CC :

Challenges include creating teams of researchers who will collaborate across the two fields. I believe if we could create such teams we could

move both fields ahead with regard to prevention and a focus on health (behaviors that are health promoting), not BMI (a number) or an emphasis on intake.

 

The key to both health problems involves the ecology in which youth are located b/c this ecology influences body image, intake, activity, self regulation and self care.

Name of idea submitter and other team members who worked on this idea : Mary Tantillo PhD PMHCNS-BC FAED

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62 net votes
116 up votes
54 down votes
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Goal 4: Develop Workforce and Resources

Translational training programs

The strategic vision to enhance translation and to enhance the workforce both require training that spans the scope of basic science, pre-clinical development, clinical trials. We lack coherent mechanisms for training the next generation of translational researchers, some of whom may be MDs, and some PhDs. A program should provide cross-training of Clinical Fellows and Postdocs to reflect the needed interactions between ...more »

Submitted by (@wjones7)

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 impact will trainees with more comprehensive exposure and involvement in translation of science from the bench to bedside. MDs will spend more time in labs or involved in pre-clinical work, PhDs will become CITI certified and assist with enrollment of clinical trials and trial design. Journal clubs will span the sciences, the clinical practice and the translational realm including regulatory and industry considerations. Trainees can use this background whether they go on in medicine, science, translation, or industry to fit and contribute to an increasingly translational medical bioscience field.

Feasibility and challenges of addressing this CQ or CC :

Feasibility must include a academic medicine environment active in translational biomedical science such that the mentors can include scientists, physicians and physician/scientists, some of whom are translators. Some of the scientists should be from industry and perhaps projects and funding can involve industry/Pharm as well these will benefit from an educated workforce. Challenges involve individuals at the sites putting the right teams together, but many Universities are doing this with incubators and translational units at present. This will further the clinical involvement to include Fellows in Fellowship programs in Cardiology, Medicine and Surgery.

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

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27 net votes
38 up votes
11 down votes
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Goal 2: Reduce Human Disease

RFA on EC-cardiomyocyte interactions in the mechanisms and treatments of cardiovascular diseases

Often under recognized, the cardiac endothelial cells are highly abundant in the heart, and may have important roles in modulating cardiac function, besides simply serving as structural component of blood vessels. Evidences of ours and others have indicated an emerging role of cardiac endothelial cells signaling to cardiomyocytes to mediate important pathophysiological responses. Nonetheless, detailed mechanisms of ...more »

Submitted by (@hcai00)

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

Details on the impact of addressing this CQ or CC :

Successfully addressing this question would no double reveal novel mechanisms and ways of monitoring treatment responses of cardiovascular disease, ultimately leading to novel drug targets, valuable biomarkers and extended new directions of basic research as well.

Feasibility and challenges of addressing this CQ or CC :

Tools of studying these cells are mostly available. Both adult cardiomyocytes and endothelial cells from the heart can be isolated and cultured, although cardiomyotyes need to used within 24 hrs and cannot be passaged. However successful preparation of these cells from WT and transgenic animals would permit co-culture experiments and mechanistic studies. These cells can also be studied using in-situ techniques either detecting molecular changes/events or dynamic interactions. Potential challenges would side in selective targeting of these cells, for example, either ECs or cardiomyocytes, once a potential therapeutic is in the testing. Nonetheless, PECAM-ab conjugated techniques have been employed to specifically deliver proteins to endothelial cells, so I am confident most of the challenges can be worked out, particularly within a RFA awardees group with frequent exchanges of ideas.

Name of idea submitter and other team members who worked on this idea : Hua Linda Cai, University of California Los Angeles

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27 net votes
30 up votes
3 down votes
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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)

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

Details on the impact of addressing this CQ or CC :

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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50 up votes
27 down votes
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Goal 2: Reduce Human Disease

Role of epigenetic mechanisms in cardiovascular disease

Are epigenetic changes the cause or the consequence of changes in cell function that contribute to cardiovascular disease? If they are the cause, what are the mechanisms that lead to changes and how do they impact disease pathogenesis? If the consequence, do they play any role in disease pathogenesis? What methods can be used to test if epigenetic changes play a causal role in disease pathogenesis? Thus far studies ...more »

Submitted by (@gko000)

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

Details on the impact of addressing this CQ or CC :

Although it is widely speculated that epigenetic control mechanisms play a critical role in disease pathogenesis, few if any studies, particularly in the CV field, have actually determined if and how epigenetic mechanisms result in functional changes in the plethora of cells that contribute to CV disease pathology. Moreover, there is a general lack of methods available to determine how specific epigenetic modifications, including histone modifications or DNA methylation of a given gene locus impacts gene expression and function of that cell. Rather, most studies have been limited to studying the effects of global alterations in chromatin structure, and/or studying global changes in epigenetic modifications average over the tens or hundreds of cell types and phenotypes within a complex tissue.

 

We must develop approaches to dissect the causal role of specific epigenetic modifications in controlling cell function in health and disease.

Feasibility and challenges of addressing this CQ or CC :

There are approaches evolving that enable one to do epigenomic edting in single cells but thus far they have not been done in the CV system, nor in vivo. They are feasible but will take a major investment to be successful.

 

Keep in mind that epigenetic mechanisms presumably regulate overall change in cell function as a consequence of exposure to disease promoting stimuli. Importantly, this is in response not only to the environmental milieu to which the cell is currently exposed, but an integral of past signals it and its predecessors experienced. Unlocking these control mechanisms will likely greatly advance our understanding of all disease processes, but particularly CV diseases which typically develop over years or decades.

Name of idea submitter and other team members who worked on this idea : Gary K Owens

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21 net votes
28 up votes
7 down votes
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Goal 2: Reduce Human Disease

COPD and co-morbidities

Society is ageing and chronic degenerative diseases including COPD are increasingly occurring together. The critical question is whether certain diseases occur together by chance or are they occurring together because they share pathobiological commonalities and mechanisms? This leads to a series of practical consequences and questions 1. Which diseases are occurring concurrent with COPD more than chance alone would ...more »

Submitted by (@bcelli)

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

Details on the impact of addressing this CQ or CC :

It is entirely possible and actually likely that several diseases manifesting in different organ systems may have shared pathobiological mechanisms. This could be the case of systemic inflammation or abnormal repair, precipitated by interaction with external agents such as pollution or smoking. This would manifest as different diseases affecting different organ systems (as could be the case of COPD and Lung Cancer) using today's taxonomy.

As it stands (taking the COPD Lung Cancer example) each is treated differently and actually strategically and clinically, they are handled as separate entitites. In all reality, if we can identify the diseases that share common pathogenetic mechanism, it is likely that we can develop common biomarker profiles that will detect disease predisposition so that early intervention can be planned.

In addition and equally important, once common co-morbidities can be grouped by pathobiology, plans can be developed by the medical establishment including health authorities to develop common approaches rather than the disjointed separate specialties that today handle each of the different organ systems.

Finally, the potential of aggregation of diseases into common pathobiological fields can reduce health care cost by integrating fields and voiding dispersion of resources.

Feasibility and challenges of addressing this CQ or CC :

It is entirely possible to use large throughput data analysis such as system network analysis to determine in a hypothesis free environment, what is the relationship amongst diseases. This analysis, that can be facilitated by the availability of electronic medical records can provide a first glance evidence of commonality amongst certain diseases.

This can be validated in other cohorts and a plan for profiling a representative sample of those cohorts in order to determine their proteomic and metabolomics profile. This will provide insight into the mechanisms responsible for the expression of the diseases and can lead to translational research aimed at identifying the mechanisms for the generation of the syndrome and potential therapeutic targets.

Once proven correct, it will be possible to identify and treat several diseases simultaneously with targeted therapy once appropriate trials have been completed.

The project here presented is already feasible and likely to offer new roads leading to a better taxonomy, identification and treatment of what now represents a puzzle of different pieces poorly interlocked.

Given the magnitude of the population that is and will be even more affected by multiple chronic diseases, this is a field that is ready for prime research efforts.

Name of idea submitter and other team members who worked on this idea : COPD and co-morbidities: Chance or Fate?

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20 net votes
22 up votes
2 down votes
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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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19 net votes
26 up votes
7 down votes
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Goal 2: Reduce Human Disease

Seeking the secret behind “resilience” to a variety of HLBS diseases

What is the secret behind the “resilience” some people have to heart, lung, blood, and sleep (HLBS) diseases?

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 :

Results of such research should reveal physiological mechanisms of resilience that could be used to develop interventions that would prevent or cure a variety of heart, lung, blood, and sleep diseases.

Feasibility and challenges of addressing this CQ or CC :

Advances in omics, clinical testing

, accumulation of large sets of clinical data and samples

, big data tools

, and increased interest from public (normal volunteers) and patients to participate in large scientific experiments make it feasible.

For instance, these may be healthy people carrying genetic mutations strongly associated with HLBS diseases (or causing rare/familial genetic diseases – these might easier to focus on first), but also people who are not hypertensive, hypercholesterolemic, or diabetic in spite of consistently making bad dietary choices, people who did not develop lung conditions in spite of high pollutant exposure, or are otherwise “protected” from other heart, lung, blood and sleep diseases. This reasoning is not very different from that used to identify ApoA Milano, or even PCSK9 or the “longevity genes”. Such information should reveal physiological mechanisms that could be leveraged to develop interventions to prevent or cure HLBS diseases.

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

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19 net votes
26 up votes
7 down votes
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Goal 4: Develop Workforce and Resources

Shall we increase the transparency of the grant review process to prevent potential biases?

Financial and intellectual conflict(s) of interest are common in academic medical sciences. Those conflicts could potentially bias decisions of study section members and change grant application outcomes. During the grant review process, financial and/or intellectual conflict(s) of interest disclosures of the study section members are not readily available to the grant applicants or the public. Should the NHBI increase ...more »

Submitted by (@escalante.patricio)

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

Details on the impact of addressing this CQ or CC :

Increased transparency in the grant review process will provide a more plain level field for all applications, including new investigators with novel ideas.

Feasibility and challenges of addressing this CQ or CC :

Public disclosure of financial (more than intellectual) conflict(s) of interest are becoming the standard in medical societies and scientific publications.

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18 net votes
24 up votes
6 down votes
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Goal 3: Advance Translational Research

Enhancing Cardiovascular Health in Childhood Through Adulthood

To enhance or maintain ideal cardiovascular health (CVH) in children and adolescents, what novel and long-term interventions can be implemented using multi-level (i.e., targeting individual, family, community, and built environment) and sustainable approaches?

Would implementation and translation of the AHA 2020 impact goals in children and adolescents enhance their CVH through adulthood?

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 :

Broad impact on the health of children and adolescents and ultimately, the health of the nation.

Feasibility and challenges of addressing this CQ or CC :

Because there are some proven modalities in small-scale studies for improving cardiovascular health in children. Most are short-term or tested mostly in adults. This CQ focuses on trials that could span 10 years from Childhood into adulthood.

NHLBI has supported numerous large-scale trials (e.g., Girls health Enrichment Multisite Studies-GEMS, PATHWAYS, Child and Adolescent Trials for Cardiovascular Health-CATCH, Trial of Activity in Adolescent Girls-TAAG, and other investigated interventions in children and adolescents along with NICHD and other ICs) that could be harnessed to support this initiative.). NHLBI is supporting multi-level trials such as the Childhood Obesity Prevention and Treatment Research (COPTR) Consortium) that could provide modalities to enhance CVH in youth. Currently, there are no long-term trials spanning childhood through young adulthood in the US on this topic. An example of such a study is The Special Turku Coronary Risk Factor Intervention Project for Children [STRIP] study in Finland. Pahkala et al., Circulation. 2013;127:2088-2096.

 

A major challenge is cost, retention in trial and long-term adherence to intervention modalities. These could be mitigated using public-private funds (cost), incentives and/or clinical trial methodologies to enhance participation and adherence. Ability to motivate children and adolescents throughout their growth could be a challenge.

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

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17 net votes
34 up votes
17 down votes
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Goal 3: Advance Translational Research

Advanced Models for Translational Cardiovascular Research and Drug Development

Although the study of the cardiovascular (CV) system has benefited significantly from the use of gene-targeted and transgenic mouse models, small rodents do not always accurately reflect human cardiovascular physiology. Many discoveries using mouse CVD models failed to translate into human applications.

Submitted by (@echenum)

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

Details on the impact of addressing this CQ or CC :

Outcomes from large animal studies are likely to translate into more favorable results in human studies. Historically, some of the most significant advances in modern CV medicine are indebted to large animals.

Feasibility and challenges of addressing this CQ or CC :

Recent advances in mammalian genome projects and gene targeting technologies enable the production of large animal models. Genome information is now available for many animal species including pigs, rabbits, dogs, cats, horses and cows. Customizable nucleases, such as Zinc Finger Nuclease (ZFN), Transcription Activator-Like Effector Nuclease (TALEN), CRISPRs (clustered regularly interspaced short palindromic repeats) associated protein-9 nuclease (Cas9) has enabled the production of gene targeted animals in many of these species lacking germline transmitting embryonic stem (ES) cells, with satisfactory results. Integration of these novel knowledge and technologies in non-primate large animals will lead to production of an array of novel models of human CVD. Research in these models will help identify and establish suitable animal models that faithfully predict the outcomes in human clinical trials of new medicines and treatments. This is believed to have a major impact in the medical research field in general and significantly move cardiovascular research and drug development forward.

Name of idea submitter and other team members who worked on this idea : Eugene Chen from University of Michigan

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11 net votes
16 up votes
5 down votes
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