Goal 3: Advance Translational Research

Best Practices for implementation of guidelines in COPD community care

How can guideline recommendations be implemented into community practice in a way that is feasible, usable, relevant, and cost-effective? (examples are use of care management, translation of chronic care model, and EMR based tools)

Submitted by (@swilliams1)

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 : Stephanie Williams, Community Program Manager, COPD Foundation

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9 net votes
11 up votes
2 down votes
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Goal 2: Reduce Human Disease

Challenge

Genetic or biologic makers that predict outcomes in pulmonary fibrosis are needed.

Validated animal models of lung fibrosis that better resemble the human condition are needed to speed up the drug development process.

An international patient registry is needed to help promote understanding of the natural history of pulmonary fibrosis and real-world impacts of interventions.

Submitted by (@swigrisj)

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

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1 net vote
6 up votes
5 down votes
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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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2 net votes
9 up votes
7 down votes
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Goal 3: Advance Translational Research

Better disease models

Many diseases of the heart, lung and blood systems are studied using animal models, often with genetically engineered mice. However, while mice get models, humans get diseases. Too many grants are devoted to curing models, a practice encouraged by many high profile journals who want to see “proof” in a standard model of disease. Much less time, effort and money will be wasted on developing ineffective therapies if focus ...more »

Submitted by (@nhlbiforumadministrator)

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

Details on the impact of addressing this CQ or CC :

Morphologic appearance is necessary but insufficient as a criterion for validating a model. Comparative “omics” should be strongly encouraged. It is a waste of resources to develop therapies based on the effects of yet another gene knock out in something as unphysiological as atherosclerotic lesions in an ApoE knock out mouse or asthma in a mouse with eosinophilic airspace disease that largely ignores the bronchial tree or the infusion “stem cells” on cardiac function in a mouse with an experimental myocardial infarct. These are simply prominent examples of widely used standard models with little real utility. Therapies based on such approaches are likely to fail. Better models that more realistically capture phenotypic features of real diseases could lead to more promising therapies.

Feasibility and challenges of addressing this CQ or CC :

Model development is not very sexy and stands a better chance of acquiring support outside the standard study section review mechanism where proposals are judged by investigators with a vested interest in (and academic career based on) using existing models, despite their poor track records.

Name of idea submitter and other team members who worked on this idea : Jordan S. Pober

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97 net votes
126 up votes
29 down votes
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Goal 1: Promote Human Health

Phenotypically accurate models of human heart, lung, blood, and sleep systems

There is a need to develop phenotypically accurate models of human heart, lung, blood, and sleep systems.

Submitted by (@nhlbiforumadministrator1)

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 : NHLBI Staff

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28 net votes
42 up votes
14 down votes
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Goal 1: Promote Human Health

The CRISPER-Cas challenge: Need to re-phenotype KO animals?

Because traditional knock out models and CRISP/Cas models often show different phenotypes for the same gene deletion, do we need to re-phenotype hundreds/thousands of knock out animal models and revisit the conclusions of many studies based on using these animal models? This research may not appear very innovative but may be very important for drawing correct conclusions about gene functions and interactions - should ...more »

Submitted by (@nhlbiforumadministrator1)

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

Details on the impact of addressing this CQ or CC :

Discovering differences in phenotypes may change many conclusions reported previously regarding gene functions and interactions.

Feasibility and challenges of addressing this CQ or CC :

New methodologies for genetic editing are available

I recently saw at least of couple of presentations showing compelling evidence that KO mice generated with CRISPR (clustered regularly interspaced short palindromic repeat) and Cas (CRISPR-associated) had different phenotypes from the corresponding existing - and widely used - KO (same gene had been knocked-out) using previous methods. This was attributed to the non-specific modification introduced by previously used constructs/methods compared to the most recent precise genetic editing methods using with CRISPER-Cas.

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

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-16 net votes
10 up votes
26 down votes
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Goal 2: Reduce Human Disease

Genomic signature in animal models

What is the genomic signature in a relevant animal model with translational significance for human pulmonary 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

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-7 net votes
6 up votes
13 down votes
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Goal 2: Reduce Human Disease

Making It Real: Affordable Physiologically Relevant In Vitro Environments

We have done the best we can to mimic the human internal environment in vitro for the discovery, testing, and validation of therapeutics, but there is a critical need to do better. The use of more complex cell-based in vitro models is the result of the recognition of how little predictive power there is in current experimental conditions, even with animal models. With an in vitro environment that goes beyond temperature ...more »

Submitted by (@ahenn0)

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

Details on the impact of addressing this CQ or CC :

Physiologically relevant in vitro environments could potentially impact research on every tissue type, disease, and intervention, including transfusion-based treatments. Basic research, drug-testing, and translational medicine would all be fundamentally altered. Individualized medicine, cellular therapies, and regenerative medicine could all benefit from in vitro conditions that best support the care of the patient's cells and guide those cells in the direction needed for effective treatment.

Feasibility and challenges of addressing this CQ or CC :

Research and Industry are in the early stages of developing the techniques and know-how needed to address the technical challenges in establishing human-relevant in vitro environments. We already have the technology to control in vitro oxygen and other critical gas components. Mimicking cell-cell interactions and variable cell states such as states of differentiation or stress are areas under active research. Computational and analytical techniques are being developed that can gain insight from large data sets. More of a challenge may be assessing distant effects like metabolism of drugs by the liver or potential drug and cellular interactions with the external environment. However, making a human-predictive in vitro environment affordable is the challenge that could define success or failure of any particular approach. It is feasible within the next ten years to have truly predictive in vitro environments for drug cellular therapy development.

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-4 net votes
10 up votes
14 down votes
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