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 3: Advance Translational Research

Molecular determinants of vascular wall development and aneurysm formation that can be used as markers for early diagnosis

To increase the potential of translating basic research discoveries into the clinic, there is a need to discover molecular biomarkers that confer risk for aneurysms and vascular dissections. The creation of a nation-wide biorepository of well-defined tissue and plasma samples along with research utilizing these tissue samples employing state-of-the art proteomics, genomics and development of appropriate mouse models will ...more »

Submitted by (@dstrickland)

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 challenge is the coordination of all components of the Project (i.e. development of a national biorepository along with coordination of proteomics and genomics analysis as well as proof of concept in animal models).

Feasibility and challenges of addressing this CQ or CC :

This process is not feasible via the R01 funding mechanisms. The feasibility of addressing this critical challenge is excellent provided adequate resources are provided.

Name of idea submitter and other team members who worked on this idea : Dudley Strickland and Selen Catania Muratoglu

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Goal 3: Advance Translational Research

Animal Models for Translational Research and Drug Development

There is a need to identify and develop suitable animal models (e.g. larger, non-primate animal models) that faithfully predict the outcomes of new medicines and treatments in heart, lung, blood, and sleep (HLBS) disorders prior to human clinical trials.

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 :

If animal models can faithfully predict the outcomes in human clinical trials of new medicines and treatments, it will reduce the economic burden for the failure of drug development.

Feasibility and challenges of addressing this CQ or CC :

Identification of current available animal models;

Development of new animal models with recent advances in mammalian genome projects and gene targeting technologies could be done over the next 5-10 years

Medical research, especially in basic discovery, has benefited significantly from the use of various animal models, such as gene-targeted and transgenic mouse models. However, many discoveries from animal models (e.g. mouse models) failed to translate into human applications.

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

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Goal 3: Advance Translational Research

Translation Research Dissemination & Implementation Frameworks

We need to identify and test the proven effective dissemination and implementation frameworks that are relevant to heart, lung, and blood disorders in order to scale up evidence-based interventions in real world settings, ultimately improving health equity among minority populations, including low income minority residents living in public housing.

Submitted by (@nhlbiforumadministrator1)

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

Details on the impact of addressing this CQ or CC :

• Ability to determine how much of an evidence based intervention can be sustained in real world settings.

• Add utilization of D&I frameworks to researcher’s core competency training skills.

• Promote long term sustainability of evidence based interventions.

Feasibility and challenges of addressing this CQ or CC :

• Researchers from the 2014 NIH’s Annual Conference on the Science of Dissemination and Implementation: Transforming Health Systems to Optimize Individual and Population Health presented compelling evidence that dissemination and implementation frameworks are an effective means to scaling up evidence based interventions.

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

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4 net votes
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Goal 1: Promote Human Health

Developing predictive models

The need for sophisticated analytic methods to address multidimensional data to facilitate the development of predictive models.

Submitted by (@rebecca.lehotzky)

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 : AHA Staff & Volunteers

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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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Goal 3: Advance Translational Research

Facilitating the translation of discovery science into proof of concepts in preclinical models

What steps can the research community take to facilitate the translation of discovery science into proof of concepts in preclinical models and in humans for diagnosis, prevention, and treatment? • Current regulatory environment • Lack of communication between discovery and clinical research worlds • Lack of training • Getting industry, academia, and NHLBI to partner; and the business model to make it happen. • Limited ...more »

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 :

• Increased number of novel therapeutics, diagnostics and devices in early phase clinical trials

• Increased impact in rare diseases and unmet needs

• Increased number of licensed IPs from academic centers

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

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17 net votes
25 up votes
8 down votes
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Goal 2: Reduce Human Disease

Rare disease therapeutics high throughput screening

Can we develop model systems for the high throughput screening of new and existing agents as possible therapies for rare diseases?

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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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 3: Advance Translational Research

Neglect of Valuable Heart Health Data

Routine bypass surgery generates left ventricle pressure and volumetric flow data which can be modeled by estimated parameters capable of determining a heart health index. This capability is also available online for the surgeon's

guidance and is applicable to any heart chamber.

Submitted by (@woneill)

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

Details on the impact of addressing this CQ or CC :

A comprehensive heart health state would be established

Feasibility and challenges of addressing this CQ or CC :

The theory has been proven multiple times, intellectual and political inertia are the roadblocks.

Name of idea submitter and other team members who worked on this idea : William ONeill, Jeffery Shuhiaber

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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

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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