Goal 3: Advance Translational Research

Implementation of Evidence-based Guidelines in LMICs

How can implementation strategies be tested in low and middle income countries for contextually and culturally adapted evidence-based clinical care guidelines with a focus on prevalent non-communicable diseases with large burdens such as sickle cell disease, hypertension, heart disease, stroke, asthma, and COPD?

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 :

Evidence-based guidelines for heart, lung, and blood diseases, developed within high income countries are challenging to implement within low and middle income countries because delivery capacity and health care infrastructure is often limited. Contextually, culturally and language adapted guidelines implementable within low and middle income countries can impart substantial benefit while distributing more evenly global knowledge of proven effective interventions while improving health equity. Proven effective interventions would get delivered in an effective manner across low and middle income countries which will improve heart, lung, and blood health outcomes.

Feasibility and challenges of addressing this CQ or CC :

The NHLBI Global Health Think Tank recommended research on implementation of contextually, culturally and language-adapted clinical care guidelines in low and middle income countries and encouraged addressing this issue in the near future.

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

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8 up votes
18 down votes
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Goal 2: Reduce Human Disease

PUFA Toxicity

Our diets contain 20 times more omega-6 fatty acids than the diets of humans before agriculture, industrial solvent extraction of seed oils and hydrogenation. These acids including linoleic and arachidonic acids are precursors to eicosanoids that mediate inflammation and blood clotting and the amount in our diet has been shown to correlate with negative health outcomes. Should NHLBI fund more research into the effects ...more »

Submitted by (@shoemajd)

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

Details on the impact of addressing this CQ or CC :

Federal regulations could limit the amount of omega-6 fatty acids in foods and significantly reduce the incidence of atherosclerosis, strokes, heart attacks, asthma and autoimmune disease.

Feasibility and challenges of addressing this CQ or CC :

Evidence already exists but should be confirmed in large scale studies

Name of idea submitter and other team members who worked on this idea : James Shoemaker MD PhD

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-4 net votes
9 up votes
13 down votes
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Goal 4: Develop Workforce and Resources

Bridge “translational gap”

Provide resources and training to improve the ability of scientists to bridge the “translational gap”. Continue and expand the VITA program.

Submitted by (@societyforvascularsurgery)

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 : Society for Vascular Surgery

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5 net votes
7 up votes
2 down votes
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Goal 3: Advance Translational Research

Genetics and Genomics of Heart Disease

Identification of new genetic/genomic variants and risk genes often opens a new window to explore the fundamental molecular mechanisms underlying a disease and to develop new methods and strategies for diagnosis and treatment. Existing genomic variants and/or mutations explain only 10% to 20% heritability of common heart diseases. Much remains to be done in this important area. However, most genetic projects are discovery-driven ...more »

Submitted by (@wangq2)

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

Details on the impact of addressing this CQ or CC :

Identification of new genetic/genomic variants and risk genes often opens a new window to explore the fundamental molecular mechanisms underlying a disease and to develop new methods and strategies for diagnosis and treatment. Existing genomic variants and/or mutations explain only 10% to 20% heritability of common heart diseases. Much remains to be done in this important area. However, most genetic projects are discovery-driven and not hypothesis-driven, so that finding in this area has been extremely low. We recommend that genetics and genomics should be placed as a strong priority for NIH funding for the coming years.

Feasibility and challenges of addressing this CQ or CC :

Feasible

Name of idea submitter and other team members who worked on this idea : Qing Kenneth Wang

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5 up votes
6 down votes
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Goal 2: Reduce Human Disease

What about the impact of regulation of genes in response to external stimulation on human health

We are focusing a lot on the genes that may be protective or harmful to our lives. But what about the regulation of genes in response to external stimulations, such as psychosocial and/or environmental, that are probably more accountable for whether we live healthier or not.

Submitted by (@jiang001)

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

Details on the impact of addressing this CQ or CC :

Rationale: Years of research in the mind-heart field have set examples that looking at changes during dynamic stimulations (chronic, acute, and acute superimposed on chronic) are more meaningful for us to better understand how the body truly works. Therefore, research design in mimicking real dynamic process is necessary to truly capture the healthy or harmful phenotypes driven by genotypes. I suggest the NHLBI to establish a platform gathering resources to promote more sophisticated research from basic to clinical to better understand the underlying mechanisms of psychosocial impact on cardiovascular diseases that has come to a sizable problem for the human being in US and world wide.

Feasibility and challenges of addressing this CQ or CC :

We have performed researches that allow us to identify phenotypes that are only appearing under emotional stress testing. Currently we are examining whether certain intervention may modify these kinds of changes. Even our studies fail to demonstrate changes with intervention, the findings support future studies focusing on testing dynamic changes under stress that reflects daily living. Resting data obtained in laboratory does not truly represent what human beings experiences.

Name of idea submitter and other team members who worked on this idea : Wei Jiang from Duke University

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

Additional research needed to identify various contributors of obesity

What are the specific contributors of obesity that lead to chronic positive energy balance and surplus energy storage?

Submitted by (@mturner)

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

Details on the impact of addressing this CQ or CC :

Obesity is a health crisis of epic proportions. About 34% of adults in the US have obesity, up from 31 % in 1999 and about 15% in the years 1960 to 1980. The chronic diseases that result from obesity annually cost over $150 billion in weight-related medical bills. Reduction of obesity improves cardiovascular and other health outcomes, yet what is currently known about obesity is inadequate to combat the global obesity epidemic. A comprehensive understanding about the mechanics of obesity may help in developing more effective preventive and treatment strategies, which in turn will substantially improve cardiovascular and other health measures.

Feasibility and challenges of addressing this CQ or CC :

Years of obesity research have revealed the complex nature of this disease and its multi-factorial etiology. While research has firmly established the role of energy balance in weight gain and weight loss, it is important to discover upstream factors that predispose only certain individuals to energy imbalance. This may be addressed by further focusing on newly identified putative contributors of obesity, including but not limited to the impact of sleep deprivation, ambient temperature, age at first pregnancy, intrauterine and intergenerational factors, neuro-endocrine factors, epigenetics, environmental chemicals and endocrine disruptors, gut microbes, infections and the immune system, and social and behavioral factors associated with obesogenic behaviors. These studies may provide mechanistic insight that may also lead to the development of new pharmacological approaches. It is possible that cause-specific prevention or treatment approaches may yield more effective results than generic approaches that do not necessarily consider upstream modulators of energy imbalance, or inter-individual differences.

Name of idea submitter and other team members who worked on this idea : The Obesity Society

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8 net votes
18 up votes
10 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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38 up votes
11 down votes
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Goal 2: Reduce Human Disease

Translational and basic research on high triglycerides as an additional risk for cardiovascular disease.

Compelling Question (CQ)

Submitted by (@hwu000)

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

Details on the impact of addressing this CQ or CC :

Previous studies have focused on high cholesterol as a risk factor for cardiovascular disease (CVD). Recent epidemiologic and genetic studies with apoCIII mutation, for example, have identified significant contribution of high triglycerides (TGs) to the development of atherosclerotic CVD. In particular, the epidemics of obesity, even from young age, in the US and worldwide have caused significant increases in the prevalence of hypertriglyceridemia, which has become a serious health problem. However, how hypertriglyceridemia increases risk for atherosclerotic CVD remains largely unknown. Further translational and basic studies would be needed to examine how TG-rich lipoproteins and cholesterol-rich lipoproteins cooperate to increase the risk for CVD. Basic research would need to be conducted at integrative, cellular and molecular levels including examining how TGs are metabolized and how TG-rich lipoproteins, along with cholesterol-rich lipoproteins, cause atherosclerosis. These studies would guide clinical approach on TG- versus cholesterol-lowering therapy for prevention and treatment of atherosclerotic CVD.

Feasibility and challenges of addressing this CQ or CC :

The challenges include combining large clinical studies and basic research. Clinical studies includes confirming high TGs as an independent risk for atherosclerotic CVD, developing novel TG-lowering therapy and examining whether these novel TG-lowering therapy, with apoCIII as a target for example, would be beneficial in prevention and treatment of CVD. It is also important to examine effects of novel TG-lowering therapy on adiposity, adipose tissue function and risk of diabetes. Basic science needs to elucidate how TGs are metabolized in vivo, causing hypertriglyceridemia, and how hypertriglyceridemia increases risk for atherosclerotic CVD, and identify novel pathways for these pathophysiological processes, which would provide novel strategies for development of new therapy for CVD. Collaborative approach with great financial support will make all these feasible.

Name of idea submitter and other team members who worked on this idea : Huaizhu Wu, MD

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4 up votes
3 down votes
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Goal 2: Reduce Human Disease

what are the molecular pheontypic differences in IPF/ILD

What are the molecular phenotypic differences in blood and tissue of IPF ILD and how do they relate to disease course and potential response to therapy. There is a need to gain understanding in humans of the differences and similarities in iPF and iLD in general to eliminate the idiopathic nature and establish human targets. The challenge is coupling such research to longer term studies/outcomes and potentially clinical ...more »

Submitted by (@inoth0)

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

Details on the impact of addressing this CQ or CC :

Establishing molecular definitions for this idiopathic disease would a) provide greater clarity and definition to a what is otherwise a syndrome b) establish targets for intervention both for IPF and ILD in general c) refocus translational efforts on human setting for this purely human disease d) establish molecular relationships between IPF and outcomes e) establish intermediate biomarkers for more rapid evaluation for treatment development f) allow potential crossover development with acute lung injury fibrosis g) establish molecular relationships for crossover with human immunology studies and other autoimmune diseases with fibrotic tissue development (CAD, Glomerulonephritis, etc).

Feasibility and challenges of addressing this CQ or CC :

Challenges surround lack of a larger more comprehensive and integrative approach to studying human disease. In an uncommon disease such as IPF, mutlicenter patient enrollment and biologics acquisition must occur in conjunction with both long term longitudinal outcomes and the influence of both new standard of care therapies and novel clinical trials. The scope of studies must be larger, more pragmatic and longer than previously designed NIH clinical studies to allow for integration of translational research. The challenge surrounds failure to allow these elements to coexist. The potential very large for true ILD program with a vision for a long term integrative plan with vision rather than just individual RO1 efforts. An example would an overriding longitudinal study in which patients could enroll and participate in other projects/studies/treatment but where the patient is never lost to follow up. This as cornerstone would then allow other programatic efforts to coexist.

Name of idea submitter and other team members who worked on this idea : Imre Noth

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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

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 2: Reduce Human Disease

Why does loss of endoglin in adult blood cells lead to cardiac hypertrophy in HHT patients

Liver arteriovenous venous malformations creates a high flow shunt that over time creates high output cardiac failure with no effective treatments.

Submitted by (@mariannes.clancy)

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 : Marianne Clancy MPA, Chris Hughes PhD

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1 net vote
1 up votes
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