Goal 2: Reduce Human Disease

Blood specific diseases due to defects in ubiquitous pathways

Why are some blood diseases called by genetic mutations in ubiquitous pathways. Diamond Blackfan anemia is due to a mutation in ribosomal proteins.

Submitted by (@zon000)

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

Details on the impact of addressing this CQ or CC :

A number of blood diseases are due to signaling defects in ubiquitous pathways. Why would a ribosomal protein mutation lead to a red blood cell specific disorder. Certain anemias or myelodysplastic syndromes are due to mutations in chromatic factors. The chromatin factor defects can lead to clonal hematopoiesis.

Feasibility and challenges of addressing this CQ or CC :

A large scale centralized effort could select projects on blood specific diseases due to defects in ubiquitous pathways. A correlation of gene expression, translation, or transcription could lead to a better understanding of responses of blood cells to the stress of defects in common pathways.

Name of idea submitter and other team members who worked on this idea : Leonard Zon

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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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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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Goal 1: Promote Human Health

Cardiac Gene Networks

What is the level of intra-tissue variation of cardiac development gene regulatory networks at single cell resolution?

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

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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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Goal 2: Reduce Human Disease

Does lowering circulating lipoprotein(a) levels influence cardiovascular outcomes?

A comprehensive research strategy and plan is needed to determine the most efficient, safe, cost-effective and widely applicable strategy to decrease circulating levels of lipoprotein(a) and to determine whether lowering circulating lipoprotein(a) levels will reduce the risk of developing cardiovascular disease such as a heart attack or a stroke as well as the progression of atherosclerosis or aortic stenosis.

Submitted by (@serevill)

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

Details on the impact of addressing this CQ or CC :

Approximately 20% of the population are characterized by elevated circulating levels of lipoprotein(a), regardless of age, gender or blood cholesterol levels. Estimates suggest that up to 90% of the variation in plasma lipoprotein(a) levels could be due to genetic factors, which makes lipoprotein(a) the most prevalent inherited risk factor for cardiovascular diseases (CVD). Large-scale genetic studies have shown that Lipoprotein(a) was the strongest genetic determinant of CVD such as atherosclerosis and aortic stenosis. Lipoprotein(a) is one of the strongest predictors of residual CVD risk and has been shown to improve CVD risk prediction in several population-based studies. Lipoprotein(a) is also one of the strongest known risk factors for spontaneous ischemic stroke in childhood.

A comprehensive research strategy aiming at identifying, evaluating interaction with other risk factors, treating and educating patients with elevated lipoprotein(a) levels would result in substantial reductions of health care costs in the US and around the globe by reducing the burden of CVD while simultaneously improving the quality of life of these patients.

Feasibility and challenges of addressing this CQ or CC :

The list of pharmaceutical agents that reduce lipoprotein(a) levels is steadily increasing. There are approximately half a dozen strategies that have been shown to significantly and safely lower lipoprotein(a) levels. One of the challenges of this research strategy will be to determine which of these strategies represent the most efficient, safe, cost-effective and widely applicable approach to lower lipoprotein(a) levels and CVD outcomes.

Increasing awareness on lipoprotein(a) and CVD will also be of utmost importance for this effort as relatively few physicians perform lipoprotein(a) testing and even fewer patients are aware of their lipoprotein(a) level. The first sign of high lipoprotein(a) is often a heart attack or stroke. Our challenge will be to identify patients with high lipoprotein(a) that could be enrolled in trials of risk characterization and lipoprotein(a)-lowering.

Name of idea submitter and other team members who worked on this idea : Sandra Revill Tremulis on behalf of the Lipoprotein(a) Foundation Scientific Advisory Board

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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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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

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Goal 2: Reduce Human Disease

Predictors of Sickle Cell Disease Severity

Can better predictors of disease severity such as specific biomarkers and/or genetic polymorphisms be identified so as to help understand the course and progression of sickle cell disease in various patients?

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 high clinical variability in sickle cell disease (SCD) and the lack of sufficient data to help understand and or predict the course of an individual’s disease warrants the identification of better predictors of disease severity. The identification of predictors of disease severity, such as biomarkers, will be vital in the management and treatment of SCD, especially since more recently several plasma biomarkers and certain genetic polymorphisms have been proposed to influence specific clinical outcomes, including stroke, sickle cell nephropathy, and survival. Furthermore, studies of biomarkers or genetic markers in the context of clinical drug trials may be helpful in predicting response rates, thus allowing for more personalized therapeutic decisions.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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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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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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