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 3: Advance Translational Research

Translating cardiac development/genetics knowledge into therapy

What is needed to translate our knowledge of cardiac development and congenital heart disease genetics into novel diagnostic and/or therapeutic strategies for congenital or acquired heart disease?

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 :

Develop new therapies for congenital or acquired heart disease.

Feasibility and challenges of addressing this CQ or CC :

We are poised to take advantage of the incredible advances in our understanding of cardiac development and genetics which have resulted from the development of high throughput technologies.

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

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10 net votes
21 up votes
11 down votes
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Goal 2: Reduce Human Disease

Genetic risk factors for sudden cardiac death

What are the genetic risk factors for sudden cardiac death and failure to respond to CPR and defibrillation?

Submitted by (@rebecca.lehotzky)

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 : AHA Staff & Volunteers

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-2 net votes
2 up votes
4 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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-1 net votes
5 up votes
6 down votes
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Goal 3: Advance Translational Research

Can We Successfully Reduce the Risk Factor Burden and Atherosclerosis in Younger Individuals?

There is growing evidence that risk factors beginning in childhood and young adult life, e.g. from such studies as CARDIA, Bogalusa, etc., are primary determinants of risk of CHD in adults.

Submitted by (@kullerl)

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

Details on the impact of addressing this CQ or CC :

The levels of BP, lipoproteins, ApoB, obviously obesity, cigarette smoking, and growing risk of early age type 2 diabetes, are epidemic in the young United States population. This may result in a continued high burden of CHD in future generations in the United States. Unless something is done about controlling risk factors in younger individuals, a continued epidemic of CHD is likely.

Feasibility and challenges of addressing this CQ or CC :

The NHLBI should begin clinical trials to determine the best approaches to reducing risk factors in the younger United States population. This should include various studies of environmental modifications, better nutrition studies, improved exercise programs, and identification of host genetic susceptibility. To date, the programs have been remarkably unsuccessful and different approaches are required, especially in lower income and minority populations. The NHLBI should also begin to consider the evaluation of drug therapies for elevated lipids and BP, new drug therapies for obesity and even bariatric surgery in high risk young individuals with initial evaluation of the reduction of subclinical atherosclerotic disease, evidence of myocardial injury, e.g. elevated hs-cTnT, NT-proBNP, etc., in these high risk populations. There is little that the current approaches are very effective.

Name of idea submitter and other team members who worked on this idea : Lewis H. Kuller, MD, DrPH

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21 net votes
46 up votes
25 down votes
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Goal 2: Reduce Human Disease

High risk individual’s apparent protection from disease

Can we define the basis for high risk individual’s apparent protection from disease?

Submitted by (@nhlbiforumadministrator1)

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 : NHLBI Staff

Voting

-7 net votes
8 up votes
15 down votes
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Goal 2: Reduce Human Disease

Improving the phenotyping of the major (chronic) heart, lung, and blood diseases

Which phenotypic and molecular characteristics predict differential responses to therapy in individuals with chronic 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 :

• Enable pathophysiologically targeted therapies and prevention

• Enable subgroup assessment of intervention

• Better define gene-gene and gene-environment interactions

• Improve risk stratification

• Understand those who are protected against disease

• Inform development of better in vitro and in vivo models to assess disease and response

Feasibility and challenges of addressing this CQ or CC :

Advances in –omics, diagnostics, cell biology, imaging are ready to be applied

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

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30 net votes
42 up votes
12 down votes
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Goal 3: Advance Translational Research

Use isogenic iPS cells to advance Precision Medicine

The goals of Precision Medicine can be achieved if we determine the biological basis of disease-associated variants for NHLBI diseases. Advances in genetic research have yielded hundreds of disease-associated DNA polymorphisms, yet we lack robust methods to experimentally test their functional relevance in human cells. Determining the molecular and cellular basis of human phenotypic variation is one of the great challenges ...more »

Submitted by (@bconklin)

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

Details on the impact of addressing this CQ or CC :

Identifying how disease mutations result in cellular phenotypes will provide an experimental basis for Precision Medicine. Advances in genome engineering and iPS cell technology now offer a unique opportunity for NHLBI researchers to make a focused effort to produce isogenic disease models, to determining the function of putative disease loci. Just a few years ago, the barriers to this type of project seemed insurmountable, as iPS cells were made with damaging DNA insertions, designer nucleases were difficult to make, complex material-transfer agreements (MTAs) inhibited the open sharing of reagents, and cell-engineering methods were cumbersome. Remarkably, all of these barriers have fallen substantially in recent years, to reveal strategic new opportunities. The phenotypes are determined in isogenic human iPS-models, these observations can be applied to animal models, and human clinical studies.

Feasibility and challenges of addressing this CQ or CC :

Progress towards this goal is being made, but slow pace does not meet opportunity that the NHLBI community has. The NHLBI has a much larger opportunity than other institutes because so many genetic variants have already been determined via excellent genetic studies using robust physiological phenotypes. The genetic variants provide hypotheses that are ripe for direct experimental testing in isogenic iPS cell models. Fortunately, many diseases of interest to NHLBI can be modeled in iPS-derived tissues. Other part of NIH (e.g. NIMH, NIDA, NIAAA ) lack abundance of high probability genetic "hits" that NHLBI now has. NHLBI should take advantage of this opportunity.

Name of idea submitter and other team members who worked on this idea : Bruce Conklin

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-19 net votes
8 up votes
27 down votes
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Goal 1: Promote Human Health

Identify genetic variants of sleep/circadian disorders

Most aspects of variation in sleep and circadian rhythm are heritable. Moreover, all common sleep disorders aggregate in families. The response to sleep loss is also a highly heritable trait. Identifying gene variants for these disorders will elaborate new molecular pathways that could be targets for future interventions.

Submitted by (@jnoel0)

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

Details on the impact of addressing this CQ or CC :

Addressing this critical challenge would have the following impact. First, the information could be used to help identify these different disorders, including potentially subtypes. Addressing this challenge will lead to identification of new molecular pathways to disease. This will stimulate future research on their role and mechanisms of pathogenesis. Moreover, these pathways may be open to new drug interventions and hence new therapies for disease.

Feasibility and challenges of addressing this CQ or CC :

There is a growing number of cohorts both in the United States and internationally that have sleep phenotype data and DNA. These could be the basis of genetic studies.

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

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84 net votes
117 up votes
33 down votes
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Goal 2: Reduce Human Disease

Assessing gene knockout humans more effectively

What insights can be gathered from patients with single gene functional mutations to improve our understanding of the pathobiology of human disease?

Submitted by (@nhlbiforumadministrator)

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 : NHLBI Staff

Voting

-9 net votes
5 up votes
14 down votes
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Goal 2: Reduce Human Disease

Genetic and Molecular Tools for Drug Allergy - Hypersensitivity

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: Given that more patients are treated with newer and better targeted medications including chemotherapy, monoclonal antibodies, small molecules and others that have increased the number of hypersensitivity reactions, which ...more »

Submitted by (@wheeze)

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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-4 net votes
10 up votes
14 down votes
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Goal 2: Reduce Human Disease

Genetic variants of complex diseases in Asian American Subgroups

What are the genetic variants influencing complex heart, lung, blood, and sleep traits and diseases in Asian American subgroups?

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 :

High impact, given that in the U.S.: a) Asian Americans are the fastest growing racial/ethnic group, and b) heart diseases and chronic lower respiratory diseases are the second and fourth leading causes of death, respectively, among Asian Americans

Feasibility and challenges of addressing this CQ or CC :

Genetic and genomic technologies are currently available for such a study.

Although there is a growing number of genetic studies in Asian countries such as China, the research findings are not necessarily generalizable to Asian Americans, who differ in various ‘exposure variables’ including diet, behaviors, and environment. Furthermore, there is a need to conduct research among Asian American subgroups (see list immediately below) rather than lumping them into a single category, given the heterogeneity across subgroups. Sufficient sample sizes are needed to provide reliable estimates of gene-by-environment interactions; however, Asian Americans are often underrepresented in research studies in the U.S. Asian American subgroups, in order of highest to lowest % in the U.S.: Chinese; South Asians (ancestry from Indian subcontinent), Filipino, Vietnamese, Korean, and Japanese.

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

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-4 net votes
8 up votes
12 down votes
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