Goal 1: Promote Human Health

Developmental Origins of Adult Lung, Heart and Blood Disease

It all starts in childhood. Yet it is difficult to find funding to really study these questions because the follow up timeline is long and thus very expensive but critically important. We don't even know what the "right" way to feed infants is in the first year of life to both limit cardiometabolic syndrome but also preserve neurodevelopmental outcome. We also have just started to see the tii of the iceberg in understanding ...more »

Submitted by (@ryanr0)

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

Feasibility and challenges of addressing this CQ or CC :

We need a cohort of clinical investigators that understand that what we do in early infancy affects us later. The failure of the children's long-term study should not dissuade us from the importance of this concept.

Name of idea submitter and other team members who worked on this idea : Rita Ryan

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Goal 3: Advance Translational Research

Epigenomic Impacts of Exercise and Nutrition

Epigenomic Impacts of Exercise and Nutrition

Submitted by (@s0tyag01)

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

Details on the impact of addressing this CQ or CC :

Epigenomic Impacts of Exercise and Nutrition

Feasibility and challenges of addressing this CQ or CC :

Epigenomic Impacts of Exercise and Nutrition

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14 net votes
21 up votes
7 down votes
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Goal 1: Promote Human Health

Epigenetics and Genomics

There is a need to investigate hemoglobin biosynthesis in order to develop novel approaches to treat sickle cell disease, thalassemia, and other anemias.

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

Details on the impact of addressing this CQ or CC :

Studies on epigenetic mechanisms have extraordinary promise for the development of transformative therapeutic approaches for non-malignant hematologic disorders, however, limited progress has been made in advancing therapies to counteract the often crippling complications of these conditions. In the case of sickle cell disease, an ensemble of proteins has been implicated in mediating the epigenetic repression of gamma-globin expression, raising the possibility that antagonizing the actions of these proteins to increase gamma-globin expression may be a useful treatment strategy. However, in certain cases, some of these proteins are deemed “undruggable,” based on their structural attributes. There is a critical need to identify druggable components of the multi-step epigenetic mechanisms as well as develop better models and assays that will more effectively identify modulators of “undruggable” proteins. Given the rich proteome and improved technologies available today, studies of proteomics, metabolomics, and regulatory RNAs are likely to reveal promising translational avenues. In addition, approaches to modifying the expression of the components of this pathway are underway using developing gene therapy strategies, such as viral vectors and/or gene editing can quickly advance therapy in sickle cell disease and β-thalassmia.

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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42 net votes
62 up votes
20 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 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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Goal 1: Promote Human Health

Epigenetics and Genomics

There is a need to target epigenetic mechanisms as new treatment options for hematologic disorders.

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

Details on the impact of addressing this CQ or CC :

Advances in the field of epigenetics and the understanding of various epigenetic mechanisms has provided a completely new ensemble of therapeutic targets for treating hematologic disorders – both non-malignant and malignant. These mechanisms have enormous implications for understanding the molecular underpinnings of the normal orderly development of hematologic disorders. Although one of the greatest challenges in effectively treating hematologic disorders is the diversity of molecular abnormalities that underlie a disease, there are a number of common threads emerging, including alterations in proteins that function through epigenetic mechanisms. Additional research focusing on epigenetic alterations and emerging targets is needed to identify the role of such proteins in the development of hematologic disorders in order to design potential targeted treatments to counter their effects. This research will further lay the groundwork for precision medicine, and will help to provide more insight on potentially critical determinants of responsiveness to therapeutic regimens.

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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-2 net votes
13 up votes
15 down votes
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Goal 3: Advance Translational Research

Integration of Multiple Omics Data in Chronic Lung Diseases

Integration of multiple Omics data types (genetics, transcriptomics, metabolomics, proteomics, and epigenetics) to understand susceptibility, progression, and heterogeneity of chronic lung diseases.

Submitted by (@jdc000)

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

Details on the impact of addressing this CQ or CC :

No single Omics data type is likely to adequately describe the pathogenesis and heterogeneity of chronic lung diseases including COPD, asthma, and IPF. However, integration of these data types using systems biology and network approaches could transform the diagnosis, prognosis, and treatment of these chronic lung diseases.

Feasibility and challenges of addressing this CQ or CC :

The availability of multiple Omics data at fairly reasonable costs provides unique opportunities for multiple Omics research.

Name of idea submitter and other team members who worked on this idea : Ed Silverman, James Crapo and the COPDGene Executive Committee

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19 down votes
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Goal 3: Advance Translational Research

Translational Cardiovascular Medicine

There is a need for the NHLBI to catalyze the development of tools and shared data resources to facilitate mechanistic studies in a human model system. This includes the ability to culture human cardiac tissue, as well as generate a resource to systematically characterize and catalog the epigenome and histone marks associated with the transcriptome in normal and diseased heart tissues.

Submitted by (@stacey.rentschler)

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 in-depth characterization of complex cellular systems is often beyond the scope and capability of individual investigators working in isolation. The NHLBI research community lacks a shared tissue-specific systems biology framework resource that would accelerate the progress of individual, investigator-initiated research.

 

The Human Genome Project and subsequent sequencing projects are characterizing the structural architecture of the human genome, but the biological significance of the human genome and the characterization of functional elements that mediate gene-environment interactions and influence tissue-specific gene expression remain to be further defined.

Feasibility and challenges of addressing this CQ or CC :

Advances in the ability to culture adult human cardiac tissue for prolonged periods while maintaining normal electrical and mechanical function will enable testing of novel therapeutics to treat cardiovascular disease. Tissue-specific epigenetic modification of nucleic acids and dynamic changes in the histone code and chromatin remodeling are important determinants of the transcriptome within heart tissue. Advances in the ability to perform genome-wide analyses in human cardiac tissues to assess dynamic changes in the histone code and chromatin remodeling will enable comparison between normal and disease states.

Name of idea submitter and other team members who worked on this idea : Stacey Rentschler and colleagues, Washington University in St. Louis

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6 net votes
10 up votes
4 down votes
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Goal 1: Promote Human Health

Mapping the Vasculome

What is the best method to develop an integrated map of the expression patterns of the vasculature (RNA, protein, and epigenome) within each organ system?

 

Sampling standards and quality control are major outstanding issues.

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 :

The vasculome is comprised of a vast network of vessels that globally interacts with all of the other organ systems within the body. Disorders of the vasculature have a significant adverse effect on those organ systems and are a major source of mortality and morbidity. Systematic mapping of vasculome expression will reveal disease causality patterns that have thus far been unobserved.

Feasibility and challenges of addressing this CQ or CC :

The tools are available, the coordination is not. The NHLBI and VBHB have the expertise, the experience, and the leadership necessary to oversee the multiple studies, date collections, and organizational systems needed for mapping the vasculome.

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

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9 down votes
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