Goal 3: Advance Translational Research

The need for funding priorities and emphasis on valve disease and large-animal preclinical studies

Investigators need NHLBI support for programs that transform our approach to heart valve disease to mechanism-based prevention with large-animal preclinical studies through: an NHLBI-sponsored sponsored Heart Valve Network; development of models of genetic and acquired valve disease; a study section devoted to valve disease; and RFAs and RFPs based on Task Force priorities in mitral valve disease.

Submitted by (@rlevine)

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

Details on the impact of addressing this CQ or CC :

Improved health through mechanism-based prevention in an increasing cause of heart failure. Support for research that can lead directly to clinical applications yet has basic aims.

Feasibility and challenges of addressing this CQ or CC :

With NHLBI support, the resources and talented investigators can make this possible.

Name of idea submitter and other team members who worked on this idea : Robert A. Levine, MD and member of the Leducq Mitral Network

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Goal 3: Advance Translational Research

Animal models of vascular diseases

How can we better model human vascular disease in all its complexity?

­This is key to more effective translation of both diagnostics and therapeutics. Develop improved animal models of vascular diseases including PAD, aneurysm, venous diseases, to facilitate fundamental research and preclinical development.

Submitted by (@societyforvascularsurgery)

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 : Society for Vascular Surgery

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2 net votes
3 up votes
1 down votes
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Goal 1: Promote Human Health

Promoting the Development of Animal and Cellular Model Systems

NHLBI might consider creating incentives for the development of core labs and national facilities to promote development of animal and cellular model systems that mimic lung injury, repair, and regeneration.

Submitted by (@skrenrich)

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 : Cystic Fibrosis Foundation

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Goal 2: Reduce Human Disease

Interactions between anticoagulant therapy and antiretroviral drugs

Cardiovascular pathology has become a major problem in the management of the HIV-infected patient during the ART era. A large number of HIV patients will receive anticoagulants drugs for secondary prevention of cardiovascular disease. It is therefore critical to understand the interactions between antiretroviral therapy and anticoagulant therapy to safely treat HIV patients.

Submitted by (@pandrea)

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

Details on the impact of addressing this CQ or CC :

With over 50% of HIV-infected patients in the US anticipated to be > 50 years of age by 2015, the overall risk of CVD will be significantly higher and could become the main challenge for the management of chronic HIV infection. A large number of HIV-infected patients with CVD will therefore need treatment for primary and secondary prevention of atherothrombotic events. The secondary prevention of CVD almost invariably includes prescription of one or multiple anticoagulants drugs. It is therefore conceivable that anticoagulant therapies will be frequently associated with ART for the management of HIV patients, which already developed CVD. The interactions between these therapies are not well studied and are critical for the management of the HIV-infected patients.

Feasibility and challenges of addressing this CQ or CC :

Feasibility: 1) retrospective studies on a large number of HIV patients that had cardiovascular events and were treated with antiretroviral drugs; 2) prospective studies comparing different antiretroviral regimens associated with the most current anticoagulant therapy recommended for secondary prevention of CV disease; 3) use of animal models of AIDS for testing new anticoagulants and the interaction with the antiretroviral drugs.

Name of idea submitter and other team members who worked on this idea : Ivona Pandrea

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Goal 2: Reduce Human Disease

Biology of the intact alveolar wall – the new frontier in lung research

HOW DO WE STUDY THE BIOLOGY OF THE INTACT ALVEOLAR WALL IN THE CONTEXT OF LUNG DISEASE AND REPAIR?

Submitted by (@jb3900)

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

Details on the impact of addressing this CQ or CC :

SEE UPLOADED FILE

Feasibility and challenges of addressing this CQ or CC :

SEE UPLOADED FILE

Name of idea submitter and other team members who worked on this idea : JAHAR BHATTACHARYA

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Goal 3: Advance Translational Research

Animal Models for COPD -- Core Facilities

COPD is a major health problem with more than 140,000 deaths per year and yet there is a relative paucity of treatments that might modify the course of this disease. In part, this is due to the poor efficiency of animal models that require months of exposure to cigarette smoke. Moreover, there are no well validated small animal models of chronic mucus hypersecretion. Funding of core facilities that could both provide ...more »

Submitted by (@rwise0)

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

Details on the impact of addressing this CQ or CC :

Funding of core facilities that could both provide support for researchers wishing to study COPD, and the development of efficient research models as well as models of chronic bronchitis would be a major advance for screening for treatments of COPD.

Feasibility and challenges of addressing this CQ or CC :

Current technology is well established for exposure of small animals to combustible tobacco smoker. However there remains to be developed standardized exposures to e-Cigarettes and Biomass fuels.

Name of idea submitter and other team members who worked on this idea : Robert A. Wise

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20 net votes
24 up votes
4 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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6 up votes
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Goal 3: Advance Translational Research

Develop relevant large animal models for various disease conditions

What is the possibility of investing funds primarily in clinically-relevant models where the findings could be translated in to human diseases?

Submitted by (@dkagr0)

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

Details on the impact of addressing this CQ or CC :

Strong emphasis on the use of a clinically-relevant large animal model would hopefully be more productive in developing better therapeutic approaches and management of patients.

Feasibility and challenges of addressing this CQ or CC :

In view of the lack of facility at many institutions and the cost involved, and the rules and regulations by the USDA and other regularity bodies, special emphasis will be required to build the animal facility at an institution. Where will the funds come from? Similar to many other core facilities set up by the NIH at various institutions, what is the possibility of developing specialized centers for testing a new idea in a clinically-relevant large animal facility?

Name of idea submitter and other team members who worked on this idea : Devendra K. Agrawal, PhD

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11 up votes
16 down votes
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Goal 3: Advance Translational Research

Funding for synthesis and screening of potentially therapeutic molecules

Currently, there are limited, if none, funding resources to synthesize and screen potentially therapeutic molecules, based on supportive findings in cells, biopsy tissues from the patients with the disease in question, and the preliminary data to support the development of a series of compounds to screen them for their pharmacokinetics, pharmacodynamics, toxicity and use in clinically-relevant large animal models.

Submitted by (@dkagr0)

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

Details on the impact of addressing this CQ or CC :

Although NHLBI-NIH and other institutes emphasize on mechanistic approach, to my knowledge, translation of the findings into the development of novel molecules is rarely pursued in a multi-disciplinary manner. this could have a significant impact on developing better therapeutic and/or management approaches of various diseases.

Feasibility and challenges of addressing this CQ or CC :

In the past, NIH has come up with many RFAs related to this issue. However, one of the major challenges has been the screening of the compounds in a model relevant to human disease. For example, in cardiovascular diseases, about 99% studies are done in mouse models. From genetic studies point of view, this is acceptable, even though now large animals are used for knock-in and knock out gene studies. However, from the screening point of view, an emphasis must be placed on clinically-relevant model, for example, swine, where most of the findings, if not all, could translated to human disease.

Name of idea submitter and other team members who worked on this idea : Devendra K. Agrawal, PhD

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Goal 2: Reduce Human Disease

New analysis methods for research using animal models

The idea that 'animal models can faithfully predict the outcomes in human clinical trials of new medicines and treatments' is highly compelling. However, due to differences (biological and non-biological) between humans and animals this goal can likely not be achieved. Not only are animals genetically different from humans, everything else is different too. Even if living quarters are shared (e.g. house pet animals), ...more »

Submitted by (@gabrielegrunig)

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

Details on the impact of addressing this CQ or CC :

Because of the differences between humans and animals, a different paradigm of expectations and analysis methodology needs to be developed. Animal models (natural and man-made) have been superbly informative for developing means to improving human health. The key to 'successful animal models' is the interpretation of the data - and the careful design of the animal studies to capture one of the essential molecular, environmental, behavioral problems that cause the human disease and to model the essential problem in the animals.

Feasibility and challenges of addressing this CQ or CC :

At the moment, the specific design of animal models and the interpretation of the data is in the hands of individual scientists. Specific guidelines could be developed for every aspect of animal experimentation and this would help to optimize the output with respect to understanding the next steps: e.g. is this data useful in basic science, in translational science, which questions need to be answered using the analysis of human individuals ? The availability of specific methods will allow us to better move between bedside to bench and back.

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

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Goal 3: Advance Translational Research

Enhancing Translational Returns With Better Animal Models and the Basic Science Needed to Support Such Efforts

Can we improve on the preclinical development of therapies through more informed choices on new animal models by linking basic science at the R01 level with national resource centers?

Submitted by (@johnengelhardt)

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 development of effective therapies for heart, lung, and blood require the appropriate animal models for testing. Mouse models have been the mainstay and for the most part very effective. But for those diseases where mice fall short, humans have become the testing ground. With the massive push for translation at NIH, clinical trials often lack proof of efficacy in animal models or are wrongly based on biology in rodents that does not apply to humans. These clinical efforts that don’t effectively translate are exhausting resources to maintain a robust RO1 pipeline on basic research. Recognizing that we must push for translation and also keep basic research funded at a high level, NIH and NHBLI needs to get more creative in taping the best animal models for the disease.

Feasibility and challenges of addressing this CQ or CC :

With new technologies rapidly expanding for transgenesis in embryos, picking the appropriate species for modeling a given disease is now becoming a reality. However, there are several barriers to growth in this area: 1) we often do not know organ physiology and stem cell biology well enough in non-rodent species, 2) the average researcher typically does not have the expertise to utilize non-rodent models in their research or to generate new genetic non-rodent models for study, 3) the costs of non-rodent disease models is high and must be strategically utilized. One potential solution is to maintain resource centers in particular key species that collaborate with basic scientists to both better understand non-rodent organ biology and work selectively to translate basic discovery into therapies. NHLBI recently had an RFA for this type of work that was discontinued. If a new RFA was designed that links funded research (and/or new research applications) through NHLBI to selected target mission diseases and the use of strategic resource centers with expertise in alternative non-rodent models, this might productively transition appropriate use of new models for the next generation of scientists. Such an RFA for example, could provide supplements to existing R01s for projects linked to resource centers and/or have specific R01 RFAs to enter into studies in new animal models or to create new models for a given purpose.

Name of idea submitter and other team members who worked on this idea : John Engelhardt

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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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10 up votes
26 down votes
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