Goal 3: Advance Translational Research

To facilitate innovation and accelerate research translation, knowledge dissemination, and implementation science that enhances public health.

Goal 3: Advance Translational Research

Leveraging PEPFAR infrastructure for CVDs

How do we go about leveraging existing infrastructure, such as PEPFAR, to reduce the risk of HLBS diseases among HIV patients and other vulnerable populations? • Common goals and deliverables between NHLBI and partners will need to be identified • The best return on investment of NHLBI funds will need to be determined • Feasible T4 translation interventions in PEPFAR funded studies utilizing HIV populations with HLBS ...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 :

• Decrease the burden of heart, lung, blood, and sleep diseases in studies funded by PEPFAR in HIV populations

• Lessons learned could be expanded to HIV populations outside of Africa

• T4 translation interventions in these populations could help reduce risk factors for heart, lung, blood, and sleep diseases leading to better health outcomes

Feasibility and challenges of addressing this CQ or CC :

• PEPFAR has identified and recruited existing HIV populations in Africa which can be leveraged by NHLBI for heart, lung, blood, and sleep chronic disease research

• Infrastructure that has received PEPFAR investments can also be leveraged to undertake T4 translation interventions

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

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Goal 3: Advance Translational Research

Increasing Regenerative Medical Strategies in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a complex, progressive condition characterized by high blood pressure in the lungs and restriction of flow through the pulmonary arterial system. Current PAH therapies mainly act of the vasoconstrictive component of the disease; however there is a widely accepted view that another contributor to the disease is an abnormal overgrowth of cells that line the pulmonary arteries, which ...more »

Submitted by (@michaelg)

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

Details on the impact of addressing this CQ or CC :

In the past twenty years, 12 PAH targeted-therapies have been approved by the FDA. This increase in disease state awareness and in the treatment armamentarium have contributed to an increase in average survival from 2.8 years to an estimated 8-10 years. However, current treatments primarily address the vasoconstrictive component of the disease and do not address the now accepted theory of post-apoptotic overgrowth of hyperproliferative cells of the pulmonary vessels. A number of circulating stem and progenitor cells, derived from the bone marrow, have been identified that could have roles in repair of the pulmonary vascular system when interacting with the quickly, abnormally growing cells in the lung vessels. Work in this area has been named as a future research opportunity in the NHLBI-ORDR Strategic Plan for Lung Vascular Research (Erzurum S, et al. 2010).

Feasibility and challenges of addressing this CQ or CC :

Basic and translational research support is needed—including high-throughput approaches such as phage display and large-scale proteomic analysis—to better understand the relationship between circulating bone marrow-derived cells, lung-resident stem and progenitor cells, and endothelial cells of the pulmonary arterial system.

Name of idea submitter and other team members who worked on this idea : Pulmonary Hyeprtension Association, Michael Gray, Katie Kroner

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Goal 3: Advance Translational Research

New treatment for HIV and HIV-related lymphoma

Highly active antiretroviral therapy (HAART), while clearly invaluable, does not halt growth or proliferation of HL, in fact, while AIDS-defining malignancies like Kaposi’s sarcoma (KS) and non-Hodgkin’s lymphoma (NHL) have declined thanks to HAART, the incidence of HL in HIV patients has actually increased, from 14 times higher than that of non-HIV patients in the pre-HAART era to 32 times higher in the HAART era. Typical ...more »

Submitted by (@dongfang.liu)

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

Details on the impact of addressing this CQ or CC :

Today, approximately 10% (over 3.5 million worldwide) of HIV-infected patients develop lymphoma. The societal cost of HIV-related HL is particularly steep. HL patients are typically young (20s-30s), likely to actively spread virus, and without treatment, represent years of lost productivity.

Feasibility and challenges of addressing this CQ or CC :

To this end, it is important to gather a team of collaborators from the fields of immunology, cancer, immunotherapy, and HIV. Through these combined expertise, we hope to lay the groundwork for novel, life-saving therapy for patients with HL in the problematic context of HIV viral infection.

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

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Goal 3: Advance Translational Research

Core funding for successful PBRNSs

Practiced-Based Research Networks (PBRNs) are critical for the conduct of pragmatic real world studies. Most PBRNs struggle to support their infrastructure. Funding is needed to support core administration and IT, i.e. electronic interfaces and data extraction, transfer and loading from multiple EHRs and PBRN registries. Continuous if not core funding is needed whether though Center (P) awards, through through NHLBI ...more »

Submitted by (@kevinfiscella)

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

Details on the impact of addressing this CQ or CC :

Pragmatic research designed to answer real world questions is best conducted in the real world of office-based practices. This type of research is critical to informing health care innovations. Dynamic registries are needed to answer questions quickly. Once these community laboratories are lost, they are expensive to replace or revive.

Feasibility and challenges of addressing this CQ or CC :

Competing priorities during an era of flat funding

Name of idea submitter and other team members who worked on this idea : Kevin Fiscella, MD, MPH

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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

How can we develop more selective immunosuppression for allogeneic hematopoietic cell transplantation?

Graft versus host disease (GVHD) remains the most significant complication of allogeneic hematopoietic stem cell transplantation (HCT). While the use of HCT has grown significantly safer and has demonstrated broad efficacy in the setting of a broad range of blood diseases, immunosuppressive therapy has not dramatically evolved since the introduction of calcineurin inhibitor-based approaches decades ago. The availability ...more »

Submitted by (@kkomanduri)

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

Details on the impact of addressing this CQ or CC :

GVHD remains a critical problem and major barrier to the more widespread utilization of HCT, especially for nonmalignant diseases, where tolerance of treatment-related mortality is understandably low.

 

There is a compelling need for novel immunosuppressive agents that can effectively limit alloreactivity mediated by donor T and B cells, while relatively sparing pathogen-specific T cells, including those mediating antiviral T cell responses important in the post-HCT interval.

 

In the past decade, drug development has facilitated the introduction into preclinical and clinical trials of a broad range of agents that in addition to targeting pathways of interest in target cells (e.g., aberrant signaling in cancer cells) may also effectively inhibit T and/or B cell responses. Examples include hypomethylating agents (e.g., azacitidine), HDAC inhibitors (e.g., vorinostat), MEK inhibitors (e.g., trametinib) and BTK inhibitors (e.g., ibrutinib). Each of these classes of agents has been demonstrated in preclinical and/or clinical studies to also limit alloreactive T cells, and/or augment regulatory T cell responses, leading to a net reduction of alloreactivity. Unlike traditional agents (e.g., the calcineurin inhibitors) these agents appear to be more selective, and in some cases may have dual benefit in reducing relapse.

 

The NHLBI can facilitate the identification and translation to clinical practice in the setting of HCT trials of novel immunosuppressive agents.

Feasibility and challenges of addressing this CQ or CC :

Research funding targeted to improving the pipeline of novel immunosuppressive agents could have immediate and dramatic impact in the field of HCT, especially impacting its application for nonmalignant diseases. Patients lacking optimal registry donors, especially those from underrepresented minority groups, will particularly benefit from improvements in immunosuppression, as patients receiving less than optimally matched donors are at much higher risk of GVHD.

 

The NHLBI can encourage and facilitate research that tests compounds that have already passed through the drug development process, but in many cases were not intended to function as immunosuppressive agents. Compelling preclinical studies have suggested that targeted inhibition of T and B cells, and/or epigenetic modifiers can lessen alloreactivity while preserving beneficial cellular immune responses and facilitating immune reconstitution.

 

It will be far easier to appropriate therapeutic agents already developed for another purpose than to do novel drug development from scratch. In many cases, preclinical studies have highlighted the therapeutic potential in immunosuppression for agents that have been developed to treat malignancies, but yielded suboptimal success. Research that encourages the development of these drugs as part of a combined immunosuppressive/immunomodulation approach may rescue such compounds, while yielding potential dramatic advances in clinical HCT.

Name of idea submitter and other team members who worked on this idea : Krishna Komanduri, M.D.

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Goal 3: Advance Translational Research

Embedding the future of regenerative medicine into the open epigenomic landscape of pluripotent human embryonic stem cells

Large-scale profiling of developmental regulators and histone modifications by genome-wide approaches have provided powerful genome-wide, high-throughput, and high resolution techniques that lead to great advances in our understanding of the global phenomena of human developmental processes. However, without a practical strategy to convert pluripotent cells direct into a specific lineage, previous studies are limited ...more »

Submitted by (@xuejunparsons)

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

Details on the impact of addressing this CQ or CC :

Large-scale profiling of developmental regulators and histone modifications by genome-wide approaches have provided powerful genome-wide, high-throughput, and high resolution techniques that lead to great advances in our understanding of the global phenomena of human developmental processes. However, without a practical strategy to convert pluripotent cells direct into a specific lineage, previous studies are limited to profiling of pluripotent human embryonic stem cell (hESC) differentiating multi-lineage aggregates, such as embryoid body that contain mixed cell types of endoderm, mesoderm, and ectoderm cells or a heterogeneous population of embryoid body-derived cardiac cells that contain mixed cell types of cardiomyocytes, smooth muscle cells, and endothelial cells. Their findings have been limited to a small group of genes that have been identified previously in non-human systems, and thus, have not uncovered any new regulatory pathways unique to human development. Although genome-wide mapping of histone modifications and chromatin-associated proteins have already begun to reveal the mechanisms in mouse ESC differentiation, similar studies in hESC are currently lacking due to the difficulty of conventional multi-lineage differentiation approaches in obtaining the large number of purified cells, particularly cardiomyocytes, typically required for ChIP-seq experiments.

Feasibility and challenges of addressing this CQ or CC :

Opportunity: Recent technology breakthrough in lineage-specific differentiation of pluripotent hESC by small molecule direct induction allows generation of homogeneous populations of neural or cardiac cells direct from hESC without going through the multi-lineage embryoid body stage. This novel small molecule direct induction approach renders a cascade of neural or cardiac lineage-specific progression directly from the pluripotent state of hESC, providing much-needed in vitro model systems for investigating the genetic and epigenetic programs governing the human embryonic CNS or heart formation. Such in vitro hESC model systems enable direct generation of large numbers of high purity hESC neuronal or cardiomyocyte derivatives required for genome-wide (e.g., ChIP-seq) profiling to reveal the mechanisms responsible for regulating the patterns of gene expression in hESC neuronal or cardiomyocyte specification. It opens the door for further characterizing, identifying, and validating functional elements during human embryonic development in a comprehensive manner. Further using genome-wide approaches to study hESC models of human heart formation will not only provide missing knowledge regarding molecular cardiogenesis in human embryonic development, but also facilitate rapid progress on identification of molecular and genetic therapeutic targets for the prevention and treatment of cardiovascular disease.

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

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Goal 3: Advance Translational Research

To Improve Clinical Practice Recommendations for Asthma

What are the strategies to improve the use of evidence-based clinical practice recommendations and thereby increase the quality of care and improve outcomes for people with asthma? • Lack of provider awareness, knowledge, agreement, and/or self-efficacy in using the guidelines • Inconsistent use of guidelines-based asthma care in clinical practice. • Scarce/limited resources and limited access to target audiences. • ...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 :

• Asthma is a chronic lung disease that affects 26 million people in the U.S., including more than 7 million children, at an estimated cost to the nation of $56 billion. Asthma accounts for 14.2 million missed work days, 10.5 million missed school days, 10.6 million physician office visits, and 1.8 million emergency department visits, and 439,000 hospitalizations each year.

• Despite widespread availability of evidence-based clinical practice guidelines for the diagnosis and management of asthma, only about half of individuals with asthma in the U.S. receive guidelines-based care.

• Identifying strategies to improve use of evidence-based clinical practice recommendations would 1) increase the number of people with asthma who receive evidence-based clinical care, 2) increase the number of health care providers who use (implement) evidence-based clinical practice recommendations, 3) increase the quality of care of people with asthma, and 4) improve outcomes and quality of life for people with asthma.

Feasibility and challenges of addressing this CQ or CC :

• Investigators could evaluate guidelines-based implementation strategies in implementation settings such as community and regional health systems, private medical practices, federally qualified health centers and other safety-net clinics, and hospitals throughout the U.S.

• Documented successful and sustainable implementation strategies could be shared more broadly and applied to future efforts to improve asthma care and control as well as reduce asthma disparities.

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

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Goal 3: Advance Translational Research

Accelerating Translational Research

NHLBI should define a strategy to promote collaborative research between clinician-scientists who perform patient-oriented research, and basic scientists who focus on the preclinical realm. There is not enough cross-talk between these two groups, and yet much to be gained from increasing interactions between the two (e.g. accelerating the translation of bench science findings into the clinic). In particular, funding strategies ...more »

Submitted by (@golan0)

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

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Goal 3: Advance Translational Research

Epidemiology of Chronic Lung Disease

Develop large epidemiologic cohorts of subjects with various types of chronic lung diseases with long-term follow-up of elements of disease progression and of related co-morbidities. These cohorts should be the substrate for comprehensive studies of genetics, omics, and biomarkers, as well as for clinical trials.

Submitted by (@jdc000)

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

Details on the impact of addressing this CQ or CC :

Detailed, high quality epidemiology of the major chronic lung diseases is seriously lacking. Very few cohorts of subjects at risk for or with chronic lung diseases have been established and as a result human data for understanding risk elements that determine disease progression and the development of new treatments for chronic lung diseases is substantially behind other fields. For example, COPD has become the third leading cause of death and is the only leading cause of death and disability that has increased in frequency consistently over the past several decades.

Feasibility and challenges of addressing this CQ or CC :

Multiple cohorts of Chronic Lung Diseases need to be established and support maintained for a large portion of the life of the cohort subjects in order to acquire the type of human data needed to address this challenge. An example of this challenge is that we know that GOLD 3 and GOLD 4 subjects have major disability and a markedly increased death rate, yet we know little about the elements that cause or are associated with risk of a GOLD 2 subject to progress to a GOLD 3 or GOLD 4 state.

Name of idea submitter and other team members who worked on this idea : Ed Silverman, James Crapo and the COPDGene Executive Committee

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Goal 3: Advance Translational Research

Personal surveillance to improve cardiac arrest outcomes

Can personal surveillance systems to prevent “unwitnessed” cardiac arrest improve outcomes?

Submitted by (@rebecca.lehotzky)

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 : AHA Staff & Volunteers

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Goal 3: Advance Translational Research

Integration of Multiple Omics Data in Chronic Lung Diseases

Integration of multiple Omics data types (genetics, transcriptomics, metabolomics, proteomics, and epigenetics) to understand susceptibility, progression, and heterogeneity of chronic lung diseases.

Submitted by (@jdc000)

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

Details on the impact of addressing this CQ or CC :

No single Omics data type is likely to adequately describe the pathogenesis and heterogeneity of chronic lung diseases including COPD, asthma, and IPF. However, integration of these data types using systems biology and network approaches could transform the diagnosis, prognosis, and treatment of these chronic lung diseases.

Feasibility and challenges of addressing this CQ or CC :

The availability of multiple Omics data at fairly reasonable costs provides unique opportunities for multiple Omics research.

Name of idea submitter and other team members who worked on this idea : Ed Silverman, James Crapo and the COPDGene Executive Committee

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