Strategic Goal: Goal 3: Advance Translational Research

Translational Bioinformatics Spanning Multiple Scales of Biologic Complexity to Implement Precision Pulmonary Medicine at the Po

What translational bioinformatics tools could be used in pulmonary medicine to allow multidimensional, multi-scale modeling of clinical and biomolecular data to assist clinical decision-making?

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 :

Deployment of bioinformatics tools to construct multi-dimensional, multi-scale models of pulmonary (mal)functioning from large heterogeneous data sets spanning biological molecules, subcellular compartments, signaling pathways, cells, tissues, organs, organ systems and clinical therapeutics trials to predict actionable precision medicine for clinicians at the point of pulmonary care.

Feasibility and challenges of addressing this CQ or CC :

A variety of existing powerful informatics methods for integrating a vast wealth of clinical and high-dimensional data across DNA to organism compartments to develop multi-scale modeling approaches to improve point-of-care precision medicine. Consistent with a continuous learning healthcare system, precision medicine modeling is recursive, tentative pending better understanding and therefore continuously learning.

Fundamental to implementation of precision medicine is the ability to extract heterogeneous data from basic and clinical research to be integrated systematically into clinical practice in a cohesive and large-scale manner. Deployment of precision medicine models to predict (mal)functioning progression and response the treatment in daily practice relies strongly on the availability of an efficient bioinformatics platform that assists in the translation of basic and clinical science knowledge.

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

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Strategic Goal: Goal 2: Reduce Human Disease

Fibrosis Across Organs: Bringing Together Investigators of Fibrosis of the Heart, Lungs and Bone Marrow

Fibrosis can affect essentially any tissue or organ, including the heart, lungs and bone marrow. Effective anti-fibrotic therapy has long been elusive, and transplantation has been the only therapy capable of restoring patient function as fibrotic diseases progress to organ failure. Although these diseases present clinically with organ-specific manifestations, they are now thought to share many common pathogenetic mechanisms. ...more »

Submitted by (@amtager)

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

Details on the impact of addressing this CQ or CC :

In the aggregate, diseases characterized by fibrosis have been estimated to account for up to 45% of developed world deaths. Fibrotic diseases addressed by the NHLBI include heart failure with preserved ejection fraction (HFpEF), idiopathic pulmonary fibrosis (IPF), and myelofibrosis (MF), among many others. Each fibrotic disease represents an area of great unmet clinical need, as patients suffer and die with no or limited effective disease-modifying therapies. The impact of developing effective therapies for each of these diseases individually would be great; the impact of developing therapies effective for the entire class of fibrotic diseases across organs would truly be enormous. The clinical burden of HFpEF is staggering – more than 650,000 new patients are diagnosed with heart failure in the US each year, half with diastolic dysfunction. Although not as prevalent, IPF and MF are particularly lethal. IPF has a median survival of approximately three years. MF is arguably the most aggressive of the myeloproliferative disorders and is associated with significantly shortened survival. Although agents such as spironolactone have been unable to treat fibrosis in HFpEF as yet, two anti-fibrotic drugs, pirfenidone and nintedanib, have now been shown to slow progression of IPF, and the oral JAK1/2 inhibitor ruxolitinib has been shown to improve MF survival. These early successes underscore the great impact that developing effective anti-fibrotic therapies will have.

Feasibility and challenges of addressing this CQ or CC :

This challenge could be addressed by funding research efforts to identify and therapeutically target fundamental pathogenetic mechanisms shared by fibrotic diseases across organs. Although fibrotic diseases present clinically with organ-specific manifestations, there has been a growing appreciation of that these diseases share many aspects of their pathogenesis. Fibrosis In many of these diseases results from recurrent or non-resolving epithelial or endothelial injury, followed by over-exuberant or aberrant mesenchymal cell responses. Across all organs, these processes result in the pathologic accumulation of fibroblasts and extracellular matrix, with distortion of organ architecture and loss of organ function. Core pathways leading to epithelial and endothelial cell injury and senescence, to fibroblast accumulation and persistence, and to altered matrix biochemical and biomechanical properties, are now being identified. Therapeutics developed to target these core pathways could have broad clinical applicability. Funding initiatives aimed at better the characterization of core fibrotic pathways already identified, the identification of new core fibrotic pathways, and the development of therapies to target core fibrotic pathways, could allow the NHLBI to simultaneously and cost-effectively address the great unmet needs of the large patients with any of the many devastating fibrotic diseases that affect the heart, lungs and bone marrow.

Name of idea submitter and other team members who worked on this idea : Andrew M. Tager

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Strategic Goal: Goal 3: Advance Translational Research

Definitive Evidence of the Effectiveness of Pulmonary Rehabilitation

What is the clinical effectiveness of pulmonary rehabilitation in reducing hospital admissions and readmissions, improving health outcomes such as exercise tolerance and dyspnea, and positively impacting patient centered outcomes. Does this effectiveness vary based on the types of settings rehab is conducted in, urban vs rural environments, the components to the program, the timing of the program and the overall support ...more »

Submitted by (@gacdk0)

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

Details on the impact of addressing this CQ or CC :

Pulmonary rehabilitation is a critical component in the treatment of COPD patients but several barriers persist that have resulted in very limited access to rehab, low referral rates for eligible patients and limited standardization of best practices within the rehab facilities that do exist. Large, definitive studies accounting for patient subgroups, site characteristics and program components can generate the level of evidence needed to expand access, educate providers and improve referral systems and create quality programs. This level of evidence is necessary to change policy to properly value the role of pulmonary rehabilitation and to convince integrated health systems in a value based market that pulmonary rehabilitation is beyond a doubt, a requirement of providing quality COPD care.

Name of idea submitter and other team members who worked on this idea : Grace Anne Dorney Koppel, COPD Foundation Board of Directors, COPD Patient Advocate

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Strategic Goal: Goal 1: Promote Human Health

Circadian-coupled rhythms in lung health

Does the homeostasis and health of the lung depend on circadian-coupled genomic function?

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 :

The circadian genome is a highly conserved system producing 24-hr rhythms in gene expression in the lung. Uncovering the molecular/cellular pathways under circadian control and their significance would provide a new generation of mechanistic understanding of lung health and development.

Feasibility and challenges of addressing this CQ or CC :

Delineating circadian mechanisms of lung function would enable new strategies to phenotype, diagnose, and mange lung disease to be developed and tested.

Over the past decade, new discovery has uncovered a mechanistic interface between the circadian clock and fundamental cellular processes including oxidative stress, cell metabolism, immune and inflammatory responses, epigenetic modification, hypoxia/hyperoxia response pathways, endoplasmic reticular stress, autophagy, and regulation of the stem cell environment. While each of these processes is involved in lung function, the significance of circadian regulation in the development and maintenance of lung health is not well-understood.

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

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25 up votes
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Strategic Goal: Goal 2: Reduce Human Disease

Developing Standards of Care for adult muscular dystrophy (FSHD, DM) patients affected by hypercarbic respiratory insufficiency

There is an unmet need for the NHLBI to foster basic, preclinical and clinical research on the pulmonary consequences of respiratory insufficiency, and specifically with hypercarbic (high CO2) respiratory insufficiency, in facioscapulohumeral muscular dystrophy (FSHD) and other adult muscular dystrophies. The adult muscular dystrophies have received insufficient attention, both from research and clinical practice perspectives. ...more »

Submitted by (@daniel.perez)

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

Feasibility and challenges of addressing this CQ or CC :

As with cardiomyopathy and arrhythmia, currently little data is available as to how to best measure/monitor, and when and how to intervene in, the respiratory complications of the adult muscular dystrophies (FSHD, DM, LGMD) using respiratory therapy, non-invasive ventilation (bi-Pap, Trilogy) or ventilation. The absence of home-based sleep studies and technologies to easily assess hypercapnia are identified as a significant gap in knowledge. Additionally, since the cardiac and pulmonary hypercarbic respiratory insufficiency complications are inextricably linked, studies of the interrelationship between cardiac and pulmonary consequences of the muscular dystrophies (congestive heart failure, pulmonary hypertension) are needed, and interdisciplinary teams of researchers may be best equipped to conduct them.

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

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Strategic Goal: Goal 2: Reduce Human Disease

Fibrosis Care Center Network and Patient Registry

Complex diseases such as interstitial lung disease and pulmonary fibrosis requires a collaborative effort to effectively characterize, appropriately diagnose, and efficient evaluate novel therapies. Similarly, basic, translational and clinical research in this field requires the integration of clinical phenotypes with biologic specimens. We propose the expanded development of the Care Center Network and Patient Registry ...more »

Submitted by (@gcosgrove)

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 envisioned impact of an integrated Care Center Network and Patient Registry is to create a resource that:

 

• Informs the understanding of interstitial lung disease (ILD), its epidemiology and natural history;

• Assists to understand treatment patterns associated with optimal outcomes that will inform an emerging standard of care and development of treatment guidelines;

• Facilitates patient and clinician engagement in support of future prospective studies;

• Furthers study of biomarkers and predictors of disease and severity;

• Documents patient experience of living with ILD as described through patient reported outcomes (PRO) including quality of life, functioning, and symptoms;

• Generates new hypotheses and new endpoints in support of future studies;

• Increases awareness of relevant issues and needs among the immediate ILD community;

• Provides the opportunity to promote and inform policies in the larger health care community in support of those with ILD

Feasibility and challenges of addressing this CQ or CC :

With the establishment of collaborations between several partners, we initiated the PFF Care Center Network and Patient Registry in 2014. The Care Center Network and Patient Registry has since expanded to 21 centers regionally dispersed throughout the United States. The challenges of effectively and efficiently investigating the cause, care and treatment of pulmonary fibrosis are predominantly those of organization and integration of effort. Expertise is present throughout the United States. We suggest that with the continued expansion of the Care Center Network and Patient Registry, those challenges will be overcome and the focus of the fibrosis community efforts can be on diligently investigating the diseases that devastatingly affect patients. An integrated repository of well-phenotyped patients and biologic specimens is the first step in Precision Medicine for patients with interstitial lung disease and pulmonary fibrosis.

Name of idea submitter and other team members who worked on this idea : Gregory P. Cosgrove, MD, The Pulmonary Fibrosis Foundation

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Strategic Goal: Goal 2: Reduce Human Disease

How can we increase the pharmaceutical clinical research of targeted therapies in pediatric PAH patients, including encouraging

Clinical research, especially randomized pharmaceutical clinical trials, poses many unique challenges compared to research in adult subjects. In pulmonary arterial hypertension, a disease characterized by high blood pressure of the lungs with increased pulmonary vascular resistance leading to right ventricular failure, there are 12 FDA-approved PAH-targeted therapies for adults. None of these medications are currently ...more »

Submitted by (@katherinek)

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

Details on the impact of addressing this CQ or CC :

Pulmonary arterial hypertension is a heterogeneous condition generally characterized by high blood pressure in the lungs and increased pulmonary vascular resistance that leads to right heart failure if left untreated. Though some causes of PAH are seen in both adult and pediatric populations, some etiologies are seen exclusively in pediatric populations, including persistent pulmonary hypertension of the newborn, bronchopulmonary dysplasia, lung hypoplasia, and alveolar capillary dysplasia. Despite these differences in disease etiology, and known physiologic differences in pediatric populations, inhaled nitric oxide (iNO) in the acute setting is the only approved medication for PAH treatment in children. A number of issues have decreased pediatric PAH pharmaceutical research, including protection of the pediatric population as vulnerable subjects, principle of scientific necessity, balance of risk and potential benefit, parental consent/child assent, and feasibility of pediatric clinical trial design and implementation. Encouraging clinical trials of existing adult medications and potentially emerging, novel agents specifically for pediatrics—either through direct sponsorship or regulatory incentives—would not only lead to better outcomes for pediatric PAH patients, but potentially to a better and more comprehensive characterization of the developing pulmonary vascular system and right ventricle.

Feasibility and challenges of addressing this CQ or CC :

Several challenges exist for addressing this critical challenge. First, there are a number of differences between conducting clinical research in pediatric populations compared to adult populations. This not only includes the broad items referenced above, but items as noted by Rose and colleagues related to clinical trial design and analysis including (1) accepted age-matched normal ranges for laboratory values; (2) requirements for the validation of clinical endpoints for the assessment of efficacy and safety; and (3) standards for long-term safety monitoring and pharmacovigilance (Rose K, et al. NEJM 2005). Sponsorship of this type of clinical research is a second concern, which could either be mitigated by direct support from the National Institutes of Health of pediatric PAH clinical trials or in regulatory changes incentivizing pediatric clinical research in rare diseases.

Name of idea submitter and other team members who worked on this idea : Katherine Kroner, Michael Patrick Gray, PHA

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Strategic Goal: Goal 3: Advance Translational Research

Effect of short-term vs. chronic pulmonary rehabilitation on patient-reported outcomes

What is the comparative effectiveness of short-term vs. chronic (indefinite) pulmonary rehabilitation on patient-reported outcomes (symptom frequency, activities of daily living, quality of life, sleep quality, exacerbations)?

Submitted by (@scerreta)

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

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Strategic Goal: Goal 2: Reduce Human Disease

In pulmonary arterial hypertension (PAH), how can right ventricular function be improved in the setting of increased afterload

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. Significant improvements have been made in medical management with through approved pulmonary vasodilator therapies. However, long-term right ventricular afterload reductions have still not yet been achieved. The process by which the ...more »

Submitted by (@katherinek)

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

Details on the impact of addressing this CQ or CC :

Understanding of many components of the PAH disease state have evolved significantly in the past thirty years. When initially described by an NIH registry, in a time where pulmonary transplantation was the only treatment for PAH, the average life expectancy of PAH patients was estimated to be 2.8 years. Since then, 12 PAH-targeted therapies have been approved by the FDA; these therapies primarily act by dilating the pulmonary arteries in order to allow blood to flow easier through the pulmonary vascular system. Despite these advances and complex therapies, long-term afterload reduction is not achievable in most PAH patients. Patients continue to die from right ventricular failure, highlighting the important relationship of the pulmonary arterial system and right ventricle. Little is known about how and why the RV progresses from hypertrophy to full RV failure, the diagnostic signs indicating early RV failure, and how best to intervene to support the failing ventricle. Knowledge in this area is critical, however, as the RV is able to recover in many patients with severe PAH after lung transplantation. The relationship between the lung vasculature and cardiac function, and specifically a characterization of RV failure, was included as a research opportunity in the Strategic Plan for Lung Vascular Research in an NHLBI-ORDR Workshop Report (Erzurum S, et al. 2010).

Feasibility and challenges of addressing this CQ or CC :

The primary challenge of addressing this CQ on how right ventricular function can be improved in the setting of increased afterload is the comprehensive analysis and support that will need to be provided, spanning from basic to clinical science. To begin, strong support of biologic characterization of the right ventricle needs to be provided. The RV is distinctly different from the more comprehensively studied left ventricle (LV), and subsequently responds differently to changes in pressure, neurotransmitters, hormones, and pharmaceutical therapies to name only a few. However, when identified, these RV biologic distinctions can be further explored to develop a better understanding of RV failure and potential points of intervention.

Name of idea submitter and other team members who worked on this idea : Katherine Kroner, Michael Patrick Gray, PHA

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Strategic Goal: Goal 2: Reduce Human Disease

How can we better understand regional tissue heterogeneity in lung disease?

Many lung diseases (IPF, COPD) are characterized by marked heterogeneity at the tissue level. Unfortunately, most of the tools we currently employ to understand lung disease are unable to elucidate the mechanisms that result in regional heterogeneity. Clinical studies and animal models, while invaluable, generally assume that all lung tissue is similarly affected based on the presence or absence of diagnostic criteria ...more »

Submitted by (@bradley.richmond)

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

Details on the impact of addressing this CQ or CC :

Emerging evidence suggests that diseases such as IPF and COPD have observable phenotypes at the cellular and tissue levels long before the disease is clinically apparent. Thus seemingly healthy patients may have some regions of the lung affected by the same pathophysiologic processes that drive clinically apparent disease. By changing the focus of investigation from the presence or absence of disease in a given patient to the presence of absence of disease in a given region, several advantages emerge: (1) pathophysiologic mechanisms may be investigated earlier in the natural history of a disease, when interventions are more likely to be of benefit; (2) early investigation favors the discovery of distinct disease subgroups that are masked in more severe disease; and (3) a single patient may provide multiple affected and unaffected disease regions, allowing him or her to serve as their own control. Recently, advances in next-generation sequencing have made it possible for the entire transcriptome of a single cell to be analyzed. It is reasonable to believe that in the next 10 years single cell epigenome, proteome, and metabolome profiling will become routine. However, it seems less obvious how these methodologies can be employed to better understand the drivers of regional differences in lung disease. While technically difficult, studies applying high-throughput technologies to the discovery of regional differences will be invaluable to our understanding of lung disease.

Feasibility and challenges of addressing this CQ or CC :

To address this critical challenge, at least five technological hurdles will have to be addressed: (1) technologies such as laser capture microdissection which allow for the isolation or cells from specific areas of the lung will need to improve; (2) technologies allowing for culture of multiple cell types on a single artificial substrate (to allow for experimental manipulation of cellular “communities”) will need to emerge; (3) collaborative networks will need to emerge whereby datasets from multiple labs can be integrated; (4) bioinformatics and statistical methods capable of filtering massive “omics” data sets from multiple cell types will need to be refined; and (5) researchers with the skills necessary to distil large descriptive datasets into testable hypotheses will need to be trained. While these hurdles are great, they must be overcome in order to translate the promise of next-generation sequencing techniques into an improved understanding of the drivers of regional heterogeneity in lung disease.

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

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Strategic Goal: Goal 2: Reduce Human Disease

what are the molecular pheontypic differences in IPF/ILD

What are the molecular phenotypic differences in blood and tissue of IPF ILD and how do they relate to disease course and potential response to therapy. There is a need to gain understanding in humans of the differences and similarities in iPF and iLD in general to eliminate the idiopathic nature and establish human targets. The challenge is coupling such research to longer term studies/outcomes and potentially clinical ...more »

Submitted by (@inoth0)

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

Details on the impact of addressing this CQ or CC :

Establishing molecular definitions for this idiopathic disease would a) provide greater clarity and definition to a what is otherwise a syndrome b) establish targets for intervention both for IPF and ILD in general c) refocus translational efforts on human setting for this purely human disease d) establish molecular relationships between IPF and outcomes e) establish intermediate biomarkers for more rapid evaluation for treatment development f) allow potential crossover development with acute lung injury fibrosis g) establish molecular relationships for crossover with human immunology studies and other autoimmune diseases with fibrotic tissue development (CAD, Glomerulonephritis, etc).

Feasibility and challenges of addressing this CQ or CC :

Challenges surround lack of a larger more comprehensive and integrative approach to studying human disease. In an uncommon disease such as IPF, mutlicenter patient enrollment and biologics acquisition must occur in conjunction with both long term longitudinal outcomes and the influence of both new standard of care therapies and novel clinical trials. The scope of studies must be larger, more pragmatic and longer than previously designed NIH clinical studies to allow for integration of translational research. The challenge surrounds failure to allow these elements to coexist. The potential very large for true ILD program with a vision for a long term integrative plan with vision rather than just individual RO1 efforts. An example would an overriding longitudinal study in which patients could enroll and participate in other projects/studies/treatment but where the patient is never lost to follow up. This as cornerstone would then allow other programatic efforts to coexist.

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

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Strategic Goal: Goal 2: Reduce Human Disease

Is there a Biomarker for the Pulmonary Fibrosis of HPS?

Hermansky-Pudlak Syndrome is characterized by a bleeding disorder as well as pulmonary fibrosis. Invasive procedures such as a lung biopsy are contraindicated due to bleeding and bronchoscopy is not without risk. Finding a biomarker would reduce the necessity for more invasive data collection while improving outcomes.

Submitted by (@dappell)

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

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