Showing 4 ideas for tag "heterogeneity"

Goal 2: Reduce Human Disease

How can we better understand regional tissue heterogeneity in lung disease?

Many lung diseases (IPF, COPD) are characterized by marked heterogeneity at the tissue level. Unfortunately, most of the tools we currently employ to understand lung disease are unable to elucidate the mechanisms that result in regional heterogeneity. Clinical studies and animal models, while invaluable, generally assume that all lung tissue is similarly affected based on the presence or absence of diagnostic criteria... more »

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

Details on the impact of addressing this CQ or CC

Emerging evidence suggests that diseases such as IPF and COPD have observable phenotypes at the cellular and tissue levels long before the disease is clinically apparent. Thus seemingly healthy patients may have some regions of the lung affected by the same pathophysiologic processes that drive clinically apparent disease. By changing the focus of investigation from the presence or absence of disease in a given patient to the presence of absence of disease in a given region, several advantages emerge: (1) pathophysiologic mechanisms may be investigated earlier in the natural history of a disease, when interventions are more likely to be of benefit; (2) early investigation favors the discovery of distinct disease subgroups that are masked in more severe disease; and (3) a single patient may provide multiple affected and unaffected disease regions, allowing him or her to serve as their own control. Recently, advances in next-generation sequencing have made it possible for the entire transcriptome of a single cell to be analyzed. It is reasonable to believe that in the next 10 years single cell epigenome, proteome, and metabolome profiling will become routine. However, it seems less obvious how these methodologies can be employed to better understand the drivers of regional differences in lung disease. While technically difficult, studies applying high-throughput technologies to the discovery of regional differences will be invaluable to our understanding of lung disease.

Feasibility and challenges of addressing this CQ or CC

To address this critical challenge, at least five technological hurdles will have to be addressed: (1) technologies such as laser capture microdissection which allow for the isolation or cells from specific areas of the lung will need to improve; (2) technologies allowing for culture of multiple cell types on a single artificial substrate (to allow for experimental manipulation of cellular “communities”) will need to emerge; (3) collaborative networks will need to emerge whereby datasets from multiple labs can be integrated; (4) bioinformatics and statistical methods capable of filtering massive “omics” data sets from multiple cell types will need to be refined; and (5) researchers with the skills necessary to distil large descriptive datasets into testable hypotheses will need to be trained. While these hurdles are great, they must be overcome in order to translate the promise of next-generation sequencing techniques into an improved understanding of the drivers of regional heterogeneity in lung disease.

Name of idea submitter and other team members who worked on this idea Bradley Richmond

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Goal 1: Promote Human Health

Control of the molecular and cellular characteristics of regional variations in the lung

What are the regional variations in cellular and molecular characteristics (from epigenetics to microbiome) in the lung, and what controls these variations?

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

Details on the impact of addressing this CQ or CC

Advance in this research will help to understand the heterogeneity of lung disease

Feasibility and challenges of addressing this CQ or CC

Novel technologies, e.g. single cell analysis and imaging have been developed to get high resolution characterization of the cells in the lung.
Many lung diseases are heterogeneous with regional variations, which are not fully characterized at the molecular and cellular level. Mechanisms underlying the formation of the regional variations are also poorly understood.

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

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Goal 3: Advance Translational Research

Understanding heterogeneity in ARDS

ARDS is a syndrome, yet we treat it as though it was a single clinical disease. There has been success in improving the process of care for patients with ARDS, but no real progress on address the underlying process. For successful therapies to influence the disease process, we need to be able to distinguish the mechanisms active in individual patients and so that we can design and test interventions targeting the specific... more »

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 ability to target specific pathways based on subgroups would greatly enhance the opportunity to identify effective therapies and would decrease the burden of new therapies for individuals who would be less likely to benefit.

Feasibility and challenges of addressing this CQ or CC

The complexity of the clinic picture in these patients, uncertainty as to exact etiology and variation in clinical care all raise important obstacles. However, it is feasible and important to address the challenge. It may possible to address this challenge by collecting biomarkers as part of a large multicenter study. Big data approaches in which clustering can identify common groups of patients are very appealing as well. Because the syndrome is highly complex and involves multiple cellular abnormalities, it is unlikely that a single simple marker will provide an answer.

Name of idea submitter and other team members who worked on this idea Rob Paine

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