Goal 3: Advance Translational Research

Next Stage of COPD Discovery

1) Refinement of COPD subphenotypes for therapeutics, diagnostics and mechanistic interrogation. The NIH should encourage a strong focus on a) rigorous, mechanistically-reinforced definitions (chronic bronchitis, emphysema (with and without obstruction), frequent exacerbators, combined pulmonary fibrosis and emphysema) and 2) the development and optimization of animal model systems that replicate the different subphenotypes. ...more »

Submitted by (@lungmatbio1)

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 we could develop less costly and time consuming cell and animal models of COPD that reflect meaningful subphenotypes, we would be able to not only probe basic mechanism but also have reliable test platforms for candidate therapies.

There is typically a major obstacle between the acquisition of big data from observational disease cohorts, often broad but superficial, and the translation of these findings to basic discovery efforts. The clinical researchers speak a different language than the basic investigators and traversing this chasm with grant enticements might prove helpful.

Feasibility and challenges of addressing this CQ or CC :

This would require some suspension of the classic mechanistic, hypothesis driven proposals to develop these research tools.

There would need to be some reconstruction of study sections to permit these combined clinical-basic grants. The translational PPG was in keeping with this but should be reinforced with smaller grant programs such as RO1 level grants.

Name of idea submitter and other team members who worked on this idea : lungmatbio1

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Goal 4: Develop Workforce and Resources

Enhance funding for population and public health research

Many challenges posted here focus on increasing translation and development of interdisciplinary teams. Diverse backgrounds and epidemiological training makes population and public health scientists ideal candidates to connect teams in different areas of research around translation to human health. While funding exists specifically for career development of physician and pre-clinical scientists, none exists for epidemiologists. ...more »

Submitted by (@mmongrawchaffin)

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

Details on the impact of addressing this CQ or CC :

NHLBI is currently investing heavily in training epidemiologists at the PhD and postdoctoral level, but may be losing those researchers during the transition to independence and mid-career stages. Compared to those with clinical backgrounds or basic science skills, PhD epidemiologists rarely have alternative resources to fall back on when NIH funding is reduced and may have less interest in joining industry if their primary research interest is improving public health at the population level. This may make epidemiologists particularly vulnerable to leaving the field of health research. Dedicated funding that prioritizes human studies and population level research would help retain well-trained epidemiologists whose primary dedication is to improving chronic disease outcomes.

Feasibility and challenges of addressing this CQ or CC :

While the current level of funding is a challenge to everyone working in science right now, adding funding mechanisms specifically for epidemiology like those that already exist for clinician scientists and pre-clinical research could play an essential role in maintaining the pace of innovation and implementation of research.

Name of idea submitter and other team members who worked on this idea : Morgana Mongraw-Chaffin

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Goal 2: Reduce Human Disease

The relationship between genetic variation and disease mechanisms

What is the contribution of individual differences in RNA processing to disease causation, disease modification, disease susceptibility, and positive or negative responses to therapies? Studies using genome sequencing combined with RNA-seq have determined that genetic variation affects regulation of RNA processing as frequently as transcriptional regulation. While transcriptional networks are well defined in heart development ...more »

Submitted by (@tcooper)

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

Details on the impact of addressing this CQ or CC :

There are two areas of impact. First is to develop a better understanding between the effect of genetic variation on RNA processing and how individual differences in RNA processing translate into "phenotype" such as disease causation, disease modification, disease susceptibility, and positive or negative responses to therapies. Genes are filled with cis acting elements that are required for specific patterns of RNA processing. Variation that affects these cis elements are now known to produce different splice variants or mRNAs with different stabilities between individuals. This mechanism translating genotype to phenotype has not been explored. Second is to understand the RNA processing networks as well as we understand transcriptional networks during heart development and in heart disease. This understanding is very likely to provide previously unknown therapeutic approaches and targets.

Feasibility and challenges of addressing this CQ or CC :

The high through put approaches available to compare genome and transcriptome sequences,computational approaches to predict the cis elements for RNA processing, high throughput analysis for RNA binding proteins and RNA structure have provided the tools necessary to perform genome-transcriptome comparisons as a starting point. Current exome/genome analysis ignores the influence of genetic variation in RNA processing. The tools are available. The first challenge is to decide on the question and there are two areas: One- what is the role of RNA processing in heart disease/how can RNA processing be used as a therapeutic target and Two - how much does differences in RNA processing (in addition to transcription) contribute to individual phenotypic differences relevant to disease?

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

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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

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 3: Advance Translational Research

Genome Editing and Gene Therapy

There is a critical need for the establishment of strategies that will determine the efficacy, safety, and toxicity of genome editing techniques specifically in hematologic diseases.

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

Details on the impact of addressing this CQ or CC :

Inherited monogenic hematologic diseases such as hemophilia, beta-thalassemia and sickle cell disease are prime targets for future application of genome editing technology. However, studies are still needed to advance our understanding of the biology of genome editing as well as determine which other disorders are amenable to genome editing correction. Emphasis on preclinical research that focuses on determining the accuracy, safety and efficiency of this technology in order to help minimize off-target mutations and reduce toxicity, is essential for effective translation of this technology into the clinic. Once preclinical efficacy is established, support will be needed for clinical vector production, toxicity testing of the vectors/reagents used, and the performance of clinical trials. The gene correction strategies developed for inherited disorders will also be attractive for other hematologic diseases, and autoimmune disorders like lupus, rheumatoid arthritis, and type I diabetes). There is also a critical need for supporting preclinical validation studies, scale-up and GMP cell manufacturing, all of which could be shared infrastructures across multiple diseases in the NHLBI portfolio.

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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Goal 3: Advance Translational Research

Genome Profiling

How can proper infrastructure be designed to host sequencing data from hematologic diseases so as to enable its efficient interpretation and use in clinical care?

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

Details on the impact of addressing this CQ or CC :

Accurate and consistent analysis of genetic data is crucial for both basic research and clinical applications, however, the complexity of sequence mutations in several blood disorders as well as the immense amounts of raw data produced during the sequencing and analysis process, make accurate bioinformatics analysis a challenge. Furthermore, the lack of consistency in the analysis of the non-coding genome and variations in correlating this information with transcriptional and epigenetic data pose an additional challenge in obtaining a comprehensive portrait of various hematologic diseases. To overcome these challenges, content-rich portals that can offer cost-effective and regulated access to raw genomic data for interrogating and sharing sequencing results without compromising patient privacy must be designed. Also, the biologic and clinical relevance of genetic alterations found in these portals must be reliable and sufficiently comprehensive in order to foster proper interpretation.

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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Goal 3: Advance Translational Research

Roadblocks to discovery and translation in lymphoma

What are the central infrastructure and research roadblocks that are preventing transformational discoveries in lymphoma

Submitted by (@dweinstock)

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

Details on the impact of addressing this CQ or CC :

Outlined in the attached manuscript published by a committee of experts organized by the American Society of Hematology

Name of idea submitter and other team members who worked on this idea : David Weinstock for the Steering Committee of the 2014 ASH Meeting on Lymphoma Biology

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Goal 3: Advance Translational Research

Integrate mechanistic and translational research

Other entries have asked for support for translational research. To be successful, this must be integrated with mechanistic research. Ideally. MD-PhD teams would get together. Challenges in translation: find formulation, preclinical toxicology, phase I trials to establish safety, biomarkers. Challenges in mechanism: RNA-Seq, Chip-Seq of relevant cells, KO mice by Cas-CRISPR, deep expertise in the relevant discipline.

Submitted by (@klaus0)

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

Details on the impact of addressing this CQ or CC :

Translation alone is fishing in the dark, with low likelihood of success. Mechanistic alone is just science for the sake of science, because academic careers are promoted by high profile publications. The NHLBI can change this!

Feasibility and challenges of addressing this CQ or CC :

The NHLBI can change this by giving dual awards to qualified teams. Basically and R01 for the mechanistic work ($ 250 K per year for 5 years) coupled with funding for translational research (probably $ 6 m for a typical program to reach phase I)

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

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Goal 3: Advance Translational Research

Advancing the preservation of cellular therapies

Cell therapies are produced in specialized facilities and the viability/function of the cells must be retained in order to permit transportation to the site of use, coordination with patient care, etc. Current options for preserving cells are limited. Conventional methods of cryopreservation may result in poor post thaw function and are difficult to use at the point of care. Liquid storage of cells is typically limited ...more »

Submitted by (@hubel001)

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

Details on the impact of addressing this CQ or CC :

Recent analyses suggest that the pool of patients who could benefit from stem cell-based therapies could be as high as 100 million. The actual number of patients receiving stem cell therapies is actually substantially lower than that (< 500,000). it has been postulated that one reason for the gap between the potential patient pool and the actual patient pool has resulted from poor methods of preservation. The failure of recent clinical trials using mesenchymal stem cells support that hypothesis.

Feasibility and challenges of addressing this CQ or CC :

When developing a cellular therapy, supply chain issues (e.g. preservation) is frequently ignored until the failure of a clinical trial. If preservation issues are addressed concurrently with the development of a cellular therapy, the feasibility of addressing the issue is high.

 

There are two critical challenges to addressing this critical challenge: (1) preservation studies are not considered 'sexy' and therefore score poorly in conventional study sections; and (2) organizations developing a cellular therapy do not have a team member with expertise in preservation.

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

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Goal 1: Promote Human Health

Transforming Transplantation with RISC

What is necessary to reprogram the immune system to improve transplant outcomes of hearts, lungs, and hematopoietic cells? While NIAID is a major funder of immunology research, we are a major contributor to stem cell research. Our resources could be combined, where NIAID would support this approach for autoimmune diseases, and we would support work in tolerance for transplants. If the NCI also wants to collaborate on ...more »

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 :

This innovative and transformative proposal could improve tolerance to many different types of transplants.

Feasibility and challenges of addressing this CQ or CC :

In 2002, Hochedlinger and Jaenisch (Nature 415:1035-1038) created a mouse by nuclear transplantation from a mature B-cell. This was proof of principle that the immune system can be reprogrammed entirely. Since then there has been little work in this area, but Reprogramming Immune System Cells (RISC) is risky but promising.

A second approach involves mechanisms that cancer cells use to evade immune detection. While most cancer research works to restore immune competence for therapy, the basic biology of evading immune detection could be exploited to improve tolerance. These approaches could be tested in an animal model in 5 years.

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

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Goal 3: Advance Translational Research

Impactful GH Research to reduce heart, lung, blood, sleep diseases worldwide

We have characterized the risk factors associated with heart, lung, blood, sleep diseases from various papers and reports; what is needed for this information and translation research to be used to reduce morbidity and mortality globally?

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 :

Global reduction of heart, lung, blood, sleep diseases

Feasibility and challenges of addressing this CQ or CC :

Identify and form partnerships with nongovernmental organizations, Ministries of Health and other partners and develop an implementation strategy collaboratively to reduce risk for heart, lung, blood, sleep diseases globally within 10 years. This could use the framework of the previously announced ARRA “Grand Challenges”.

 

Common goals and deliverables between NHLBI and partners will need to be identified

 

Common milestones should be delineated at the outset

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

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