Goal 2: Reduce Human Disease

Biomarkers of Pulmonary Hypertension

What are informative and clinically relevant biomarkers of pulmonary hypertension (PH)?

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 :

This research emphasis would help identify novel pulmonary hypertension biomarkers of disease risk and progression that can be used for early detection or as outcome measures in prevention trials or treatment of PH, which is a disease currently still not curable with high mortality rate.

Feasibility and challenges of addressing this CQ or CC :

NHLBI Division of Lung Diseases just launched the multi-center PVDOMICS research program last September that will enroll ~1,500 patients in the next 5 years for deep phenotyping PH. PVDOMICS will provide a perfect foundation and platform for this proposed featured study about informative and clinically relevant biomarkers of PH, and make answering this proposed question more feasible in the next 5-10 years.

Although significant advances in the treatment of pulmonary hypertension have been made in the past two decades, currently pulmonary hypertension remains a devastating disease without many clinically relevant and specific biomarkers available. Novel new informative and clinically relevant pulmonary hypertension biomarkers would greatly help advance the subtype-specific early diagnosis and precision treatment of this disease that could potentially decrease the mortality of PH.

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

Voting

75 net votes
87 up votes
12 down votes
Active

Goal 2: Reduce Human Disease

Development of right ventricular-targeted therapies in pulmonary arterial hypertension (PAH)

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. A great increase in the treatment armamentarium has been noted for this rare disease in the past 20 years, with 12 new PAH-targeted therapies. Though these therapies do improve cardiac performance, this is most likely due to their primary ...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 :

Since 2006, 12 medical therapies for PAH have been approved by the FDA, which have increased survival of this rare disease from around 2.8 years to approximately 9 years; these therapies primarily act by dilating the pulmonary arteries in order to reduce pulmonary vascular resistance to blood flow. However, patients continue to die from right ventricular failure, highlighting the important relationship of the pulmonary arterial system and right ventricle (RV). Despite patients ultimately dying from RV failure, little is known about the effect of the currently available PAH-targeted therapies on RV functional support. Prostacyclins, PDE5i, and sGC agonists are thought to enhance RV contractility—though the long-term effects remain unknown—while ERAs are thought to reduce it. The direct RV effect of some potential therapies targeting the pseudo-malignancy theory of PAH is a concern, as these therapies seek to reduce the hypertrophy and angiogenesis that may actually be supporting the adapting RV. Further, therapies targeting the ventricle directly have historically been centered on the LV—for example β-adrenergic receptor blockers and RAS inhibition—and either remain controversial or without data in the RV. There remains no identified RV-specific therapy to either provide support through increase contractility or molecularly prevent the progression from RV hypertrophy to ultimate failure.

Feasibility and challenges of addressing this CQ or CC :

The primary challenge of addressing this CC on the lack of RV-targeted therapies for the treatment of PAH 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, and subsequently responds differently to autocrine, paracrine, neuroendocrine, pressure, and pharmaceutical changes to name only a few. However, when identified, these RV biologic distinctions can be translated and tested clinically to more comprehensively and appropriately treat the RV-arterial uncoupling ultimately leading to right heart failure: through both reduction in afterload and an increase in contractility.

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

Voting

66 net votes
75 up votes
9 down votes
Active

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

Voting

71 net votes
81 up votes
10 down votes
Active

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

Voting

-2 net votes
10 up votes
12 down votes
Active

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

Voting

9 net votes
12 up votes
3 down votes
Active

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

Voting

9 net votes
26 up votes
17 down votes
Active

Goal 3: Advance Translational Research

Regenerative Medicine 2.0 in Heart and Lung Research - Back to the Drawing Board

Stem cell therapies have been quite successful in hematologic disease but the outcomes of clinical studies using stem cells for cardiopulmonary disease have been rather modest. Explanations for this discrepancy such as the fact that our blood has a high rate of physiologic, endogenous turnover and regeneration whereas these processes occur at far lower rates in the heart and lung. Furthermore, hematopoietic stem cells ...more »

Submitted by (@jalees)

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

Details on the impact of addressing this CQ or CC :

Some barriers to successfully implementing cardiopulmonary regeneration include the complex heterogeneous nature of the heart and lung.

 

Hematopoietic stem cells can give rise to all hematopoietic cells but the heart and lung appear to contain numerous pools of distinct regenerative stem and progenitor cells, many of which only regenerate a limited cell type in the respective organ. The approach of injecting one stem cell type that worked so well for hematopoietic stem cells is unlikely to work in the heart and lung.

 

We therefore need new approaches which combine multiple regenerative cell types and pathways in order to successfully repair and regenerate heart and lung tissues. These cell types will likely also require specific matrix cues since there are numerous, heterogeneous microenvironments in the heart and lung.

 

If we rethink our current approaches to regenerating the heart and lung and we use combined approaches in which multiple cell types and microevironments are concomitantly regenerated (ideally by large scale collaborations between laboratories), we are much more likely to achieve success.

 

This will represent a departure from the often practiced "Hey, let us inject our favorite cell" approach that worked so well in hematologic disease but these novel, combined approaches targeting multiple endogenous and/or exogenous regenerative cells could fundamentally change our ability to treat heart and lung disease.

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

Voting

7 net votes
11 up votes
4 down votes
Active

Goal 3: Advance Translational Research

Develop guidelines, standard of care, new technologies for respiratory care for adult facioscapulohumeral muscular dystrophy

There is a need for NHLBI to develop guidelines, standard of care, new technologies for respiratory care for adult muscular dystrophy (facioscapulohumeral, myotonic and limb girdle) patients with undiagnosed or unforeseen hypercarbia CO2 retention in the acute setting who end up in trouble to help the families, doctors and patients navigate their way back to stable condition e.g. perhaps going forward with non-invasive ...more »

Submitted by (@daniel.perez)

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

Details on the impact of addressing this CQ or CC :

Prolonged and healthier lives. Lower costs and disease burden.

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

Voting

-12 net votes
2 up votes
14 down votes
Active

Goal 2: Reduce Human Disease

Optimization of Existing Therapies for Sickle Cell Disease

How can the safety, dosing and benefits of existing therapies for sickle cell disease such as hydroxyurea, be optimized in order to increase its efficacy and improve patient adherence?

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

Details on the impact of addressing this CQ or CC :

Hydroxyurea is a widely available disease-modifying therapy for sickle cell disease (SCD), but its effectiveness is currently limited by inadequate utilization, and less than optimal response. Research is needed to improve adherence to this evidence-based therapy and emphasis needs to be placed on determining whether therapy with hydroxyurea can prevent or even reverse organ dysfunction. In addition, research identifying new adjunct therapies to blood transfusion and hydroxyurea, as well as disease-specific therapies for co-morbidities such as kidney disease, hypertension, obstructive lung disease, and pulmonary hypertension will be valuable in the management and treatment of SCD.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

Voting

54 net votes
74 up votes
20 down votes
Active

Goal 2: Reduce Human Disease

Influence of the Gut Microbiome on Pulmonary Immunity in HIV-Infected Individuals

It has become increasingly clear that gut microbiota have a tremendous impact on human health and disease. While it is well known that commensal gut bacteria are crucial in maintaining immune homeostasis in the intestine, there is also evidence of indirect effects on the lung. Multiple studies have shown that alterations in gut microbiota can lead to severe defects in pulmonary immune responses and reduced ability to ...more »

Submitted by (@brent.palmer)

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

Details on the impact of addressing this CQ or CC :

HIV-infected individuals are at significant risk of developing and dying from infectious and non-infectious pulmonary complications. Alteration of gut microbiota have been shown to have dramatic effects on pulmonary immunity and severity of lung infections. For instance, multiple studies have indicated that probiotic treatment with certain Lactobacillus and Bifidobacterium strains results in reduced incidence and severity of upper respiratory tract infections in children. Similarly, a recent study showed that treatment with the minimally absorbed antibiotic neomycin was associated with alterations in gut microbiota composition and concomitant reduced pulmonary immunity and the inability to control Influenza infection in mice. It was recently described that HIV infection is associated with a dramatic alteration in gut microbiota and that these changes persist with antiretroviral therapy (ART). Thus, it is important to understand how these alterations may effect lung immunity, since the majority of HIV-infected individuals develop pulmonary infections. Furthermore, gut microbiota contribute to development of non-infectious complications such as atherosclerosis, metabolic disease, obesity and diabetes. It is thus highly plausible that the gut microbiota may also play a role in the development of non-infectious complications of the lung such as Chronic Obstructive Pulmonary Disease and Pulmonary Hypertension, the rates of which are elevated in HIV-infected individuals.

Feasibility and challenges of addressing this CQ or CC :

A better understanding of how alterations in gut microbiota associated with HIV infection affects pulmonary infectious and noninfectious complication could lead to therapies to protect this “at risk” group. Furthermore, manipulation of the gut microbiota in HIV-infected individuals using pro- and/or pre-biotics, antibiotics or diet modification to a composition that is associated with increased pulmonary immunity, reduced infections and lung complications are all low risk therapeutic strategies that could substantially improve lung heath in these individuals.

Name of idea submitter and other team members who worked on this idea : Brent Palmer (NHLBI-INHALD group member) and Catherine Lozupone

Voting

3 net votes
7 up votes
4 down votes
Active

Goal 2: Reduce Human Disease

What causes variation in severity of skeletal muscle, lung, pulmonary and heart system symptoms in FSHD muscular dystrophy

Loss of diaphragm function and impaired respiration is a leading driver of morbidity and mortality in the adult muscular dystrophies such as facioscapulohumeral muscular dystrophy, and therefore requires additional study

Submitted by (@daniel.perez)

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

Details on the impact of addressing this CQ or CC :

Muscular dystrophies comprise a heterogeneous group of genetic diseases often characterized by multi-systemic effects and distinct patterns of muscle involvement. While a characteristic pattern of muscle weakness has traditionally been used to define the different subtypes of muscular dystrophy, the cause for the regional distribution of muscle weakness, often with sparing of specific muscle groups, has largely remained unresolved. Moreover, many muscular dystrophies such as the most common form facioscapulohumeral muscular dystrophy, show noticeable variation in disease onset and progression, both between as well as within families. Involvement of the diaphragm and muscles of respiration often proceeds at a rate different from other striated muscles. Loss of diaphragm function and impaired respiration is a leading driver of morbidity and mortality in the muscle diseases, and therefore requires additional study in adult muscular dystrophy.

Feasibility and challenges of addressing this CQ or CC :

Studies in mice and humans have provided some evidence for genetic modifiers of disease onset, presentation and progression, but a comprehensive explanation for the observed differences in skeletal muscle, lung, pulmonary and heart system involvement and disease progression is currently lacking. Disease penetrance may be affected by genetic background or gene-environment interactions. Future studies on the identification and validation of such factors, both genetic and non-genetic (off target effects of drugs, diet, exercise), may provide insight into strategies that delay disease onset, prevent off-target effects of drugs and improve quality of life.

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

Voting

-10 net votes
6 up votes
16 down votes
Active

Goal 3: Advance Translational Research

Pulmonary Rehabilitation

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 (@fzaidi1)

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 : Farhan Zaidi, Jerry Krishnan

Voting

5 net votes
6 up votes
1 down votes
Active