Goal 2: Reduce Human Disease

Identifying Early Stages of Pulmonary Fibrosis

The majority of translational research designed to improve the lives of patients with pulmonary fibrosis has focused on studies of patients with advanced fibrotic lung disease. In contrast, little effort has been paid to understanding the natural history of pulmonary fibrosis, exploring the mechanisms/pathogenesis of the development of pulmonary fibrosis, and considering work designed to prevent the development of lung ...more »

Submitted by (@ghunninghake)

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 fibrosis has a mortality rate greater than that of most malignancies. Although medical therapy is finally available for some of these patients, this therapy, at best, results in a reduction in the rate of lung function decline and a reduced rate of mortality. Preventing the development of pulmonary fibrosis could result in substantial reductions in the morbidity and mortality experienced by those at risk.

Feasibility and challenges of addressing this CQ or CC :

Identifying patients with early stages of pulmonary fibrosis is not only feasible but is likely to be an expected result of the increase in chest CTs obtained through lung cancer screening. Increased consensus in the community about what defines early stages of pulmonary fibrosis will be needed for this field to truly move forward. It remains possible that medical and other targeted intervention trials could be initiated in patients felt to have early stages of pulmonary fibrosis.

Name of idea submitter and other team members who worked on this idea : Gary "Matt" Hunninghake

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Goal 2: Reduce Human Disease

mechansisms of post thrombotic syndrome

No good medical therapy exists to prevent and treat post thrombotic syndrome, the most common sequlae from a deep vein thrombosis. Recent trial data suggests that compression stockings do not prevent PTS, and thrombolysis is expensive and risky. The basic mechanisms related to fibrosis of the vein wall are not well understood.

Submitted by (@henke0)

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

Details on the impact of addressing this CQ or CC :

Further research into this area, both at the human and animal model level would allow potential translation of novel agents without the risks of anticoagulatnts, as well as shine light on basic fibrotic vascular disease processes.

Feasibility and challenges of addressing this CQ or CC :

Doable with both well defined human patients, and animal models of the disease that are similar to humans

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

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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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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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Goal 2: Reduce Human Disease

Impact of lung remodeling on congestive heart failure progression

End stage congestive heart failure (CHF) causes intensive lung remodeling beyond the type-2 pulmonary hypertension. CHF induced lung remodeling includes profound lung fibrosis, lung vascular remodeling and lung inflammation. Understanding CHF-induced lung remodeling is also critical to understand the right ventricular failure. However, this area is largely unstudied. Regulating CHF-induced lung remodeling and the underlying ...more »

Submitted by (@chenx106)

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

Details on the impact of addressing this CQ or CC :

To deal end-stage CHF will need team efforts from heart, lung, blood and immunology.

Name of idea submitter and other team members who worked on this idea : Yingjie Chen, Associate Professor, University of Minnesota

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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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Goal 3: Advance Translational Research

Do Alpha-1 Antitrypsin Deficiency and Cystic Fibrosis Inform COPD? Have we been looking?

Cystic fibrosis (CF) and alpha-1 antitrypsin deficiency (AATD) share phenotypic features with common COPD including airflow obstruction and airway mucociliary dysfunction. Although research in CF and AATD has advanced our understanding of those rare diseases, it has yet to explain common COPD. Do Alpha-1 Antitrypsin Deficiency and Cystic Fibrosis Inform COPD? Could therapies currently in use or under development for ...more »

Submitted by (@kerickson)

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 mechanisms leading to the structural and functional defects of common COPD have not been sufficiently clarified for rational new drug development, and disease-modifying pharmacotherapy for common COPD currently is not available. In contrast to common COPD, both CF and AATD are monogenetic conditions associated with protein misfolding and gain or loss of function, and several of the mechanisms underlying their clinical manifestations have been identified. Recent research has pointed to links between CF and AATD on the one hand and common COPD on the other.

 

"Do AATD and CF inform COPD?" was recently asked at conference that brought together investigators with interest in either CF, AATD or common COPD and provided a forum for scientific discourse among them. The proceedings of the conference will be published in the Annals of the ATS Supplements.

 

The content highlighted not only phenotypic commonalities among the three conditions but also identified key pathogenic similarities, notably CFTR dysfunction, ER stress and lung cell apoptosis. Preliminary data presented at the conference suggest that agents currently reserved for the treatment of either CF or AATD could have a broader therapeutic spectrum. For example, drugs designed to restore CFTR function in CF could benefit COPD patients with or without AATD. Conversely, alpha-1 antitrypsin, which is administered for the treatment of AATD-related COPD, could benefit CF patients and COPD patients without AATD.

Feasibility and challenges of addressing this CQ or CC :

As Andre Cantin, a scientific committee member and speaker at the conference put it “All participants recognized the value of comparing these uncommon genetic diseases with the more common environmental disease COPD and felt that the research communities should enhance their dialogue. All also recognized that it is a challenging exercise to think of one’s data in the broader context of other diseases outside of one’s usual area – something we do not do enough”.

 

This, however, is not an insurmountable challenge. The NHLBI has the resources to solicit and sponsor such research that is likely to lead to new therapeutic solutions for common COPD, a condition for which disease modifying treatment currently is lacking.

 

This compelling questions lends specifically to the strategic goal of promoting basic and translational research that links CF and AATD to common COPD. Importantly though, this platform could apply to additional uncommon genetic conditions and the opportunity to inform common disease.

Name of idea submitter and other team members who worked on this idea : K. Erickson, A. Wanner, MD

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Goal 2: Reduce Human Disease

Cystic Fibrosis

There should be a ramp up in research to address both treatments and management strategies for patient with CF.

Submitted by (@szlewishcr)

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

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Goal 2: Reduce Human Disease

Correlation between abdominal/diaphragmatic fibrosis and cardiopulmonary dysfunction in Duchenne

Is there a correlation between the development of abdominal/diaphragmatic fibrosis and the development of cardio-pulmonary dysfunction? Are there mechanisms (i.e., pulmonary excursion therapy) that may prevent/postpone the development of diaphragmatic fibrosis and subsequent pulmonary dysfunction?

Submitted by (@kathi0)

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

Details on the impact of addressing this CQ or CC :

currently there is no adequate method of evaluating the development of fibrosis in the diaphragm. Mdx mouse models have provided insight into this progression, and to a possible correlation between abdominal fibrosis and cardiac dysfunction.

Feasibility and challenges of addressing this CQ or CC :

: Maintaining cardiopulmonary function in Duchenne has been the mainstay of therapy, however little attention has been given to the accessory muscles of respiration. Supporting the muscles of respiration may prevent or postpone the ongoing process or cardiopulmonary dysfunction, resulting in an increased the lifespan, and quality of life, of people living with Duchenne. The current base of researchers addressing the cardiopulmonary issues in Duchenne, as well as the resources to identify and track patients with cardiopulmonary dysfunction, enhances the feasibility of answering this question.

Name of idea submitter and other team members who worked on this idea : Parent Projct Muscular Dystrophy

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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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Goal 2: Reduce Human Disease

Preventing or reversing myocardial fibrosis

Conduct proof-of-concept studies and explore whether strategies to reverse or prevent fibrosis are feasible.

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 challenge will lead to early studies of potential therapeutics for arrhythmias and heart failure. If successful, this would have huge impact.

Feasibility and challenges of addressing this CQ or CC :

Recent studies have identified some compelling signaling pathways that activate fibrosis so it is feasible to test them through creative experimentation.

Fibrosis and fibrogenesis in the myocardium are clear indications that heart function is either declining or progressing towards decline. Although much of the current research continues to focus on unraveling mechanisms that lead to fibrosis and activation of fibrogenesis, there is as yet less focus on potential mechanisms to prevent or reverse fibrosis. This was in part due to insufficient understanding of major causes of fibrosis and mechanisms that activate fibrogenesis. However, findings from recent studies show that there are several compelling therapeutic targets that are ready to be tested to see whether fibrosis can be reversed or prevented.

May need strategies on how to best to succeed in implementing the research - e.g., what research mechanisms, what kind of teams, what kind of expertise, etc. To fine tune this, a focused workshop for advice may be helpful.

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

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33 up votes
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Goal 2: Reduce Human Disease

Pathobiology of Lung Fibrosis

End organ fibrosis accounts for up to 45% of deaths in developed countries. In particular, lung fibrosis is a devastating disease with poor prognosis. Despite development of two new drugs, their efficacy is still limited, highlighting the need to better understand the pathobiology that accounts for fibrotic disease progression in the presence and absence of acute exacerbation or infectious drivers.

Submitted by (@bmoore)

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

Details on the impact of addressing this CQ or CC :

A better understanding of the pathogenesis of lung fibrosis may uncover new targets for therapy or identify biomarkers of disease progression.

Feasibility and challenges of addressing this CQ or CC :

Approaches should include new and established animal models and experiments utilizing patient-based samples and novel mullti-center clinical trials. Ancillary studies should accompany any clinical trial to provide biologic insight into treatment responses and failures.

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

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