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

Triggers of cellular and molecular pathway decompensation during pulmonary exacerbations.

What triggers decompensation of cellular and molecular pathways during exacerbations of chronic lung diseases?

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 :

Elucidation of molecular and cellular pathways driving and sustaining exacerbations in chronic lung diseases. Specifically, (1) discover what perturbs antecedent conditions precipitating mal(adaptive) compensatory mechanisms leading to pulmonary exacerbation including impact of heterogeneous resilience and concomitant chronic diseases and (2) clarify response heterogeneity of longitudinal molecular and cellular signature during treatment and recovery.

Feasibility and challenges of addressing this CQ or CC :

Longitudinal pulmonary exacerbation research nested with clinical care can be initiated within 1-2 years. As part of clinical care leveraging digital education/data (electronic health/medical records and attendant meaningful use requirements), an N-of-one research design could become self-sustaining within health care systems.

Pulmonary exacerbations exhibit multiple pathogenic pathways various concurrent pathophysiological pathways, and diverse clinical manifestations. Prevention and treatment of pulmonary exacerbations is hampered by this complex biology that is dynamic and appears to vary during the course of exacerbations. Progress toward precision medicine for exacerbations may require organization of a new taxonomy for disease, which reflects a set of clinically meaningful and exploitable similarities and differences between disease traits (exacerbation polypathomics).

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

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Goal 2: Reduce Human Disease

Noninvasive biomarkers for characterizing cardiovascular disease

Critical Challenge

Submitted by (@str0001)

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

Details on the impact of addressing this CQ or CC :

Phenotypical characterization of cardiovascular disease with computed tomography (CT) and magnetic resonance imaging (MR) to individualize targeted therapies for coronary artery and myocardial disease. Coronary artery disease is a major cause of patient death in the United States. Nonischemic myocardial disease includes entities with clinically heterogeneous presentations and is thus challenging to manage.

Feasibility and challenges of addressing this CQ or CC :

Currently CT and MR technology allows dynamic evaluation of the perfusion and contractility of the heart. Quantitative measures of disease burden, such as atherosclerotic plaque composition and myocardial texture imaging biomarkers (such as T1 mapping, activation mapping, flow pattern analysis, delayed myocardial enhancement), are possible. Positron emission tomography (PET)/MR, which combines metabolic with functional evaluation, is currently available and facilitates the development of targeted molecular-imaging techniques. Metrics derived from these techniques may serve to stratify patients noninvasively and direct appropriate therapies. Such imaging methods address noninvasive evaluation of cardiovascular disease, including ischemic heart disease but also myocardial diseases that include secondary and infiltrative cardiomyopathies, hypertrophic cardiomyopathy, and organ rejection in the scenario of transplantation.

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

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Goal 4: Develop Workforce and Resources

Training for radiologist researchers for effective translational research

Critical Challenge

Submitted by (@str0001)

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

Details on the impact of addressing this CQ or CC :

As targeted therapy and molecular mechanisms of disease are emerging, a mechanism to improve the ability of radiologists to perform translational research is crucial. Such knowledge is essential for collaborative multidisciplinary research that ultimately leads to imaging as disease-specific diagnostic and therapeutic tools to combat pulmonary and cardiovascular disease.

Feasibility and challenges of addressing this CQ or CC :

Knowledge in the molecular mechanisms of disease and the potential for imaging technology to advance via targeted imaging agents, positron emission tomography (PET), functional MR methods, PET/computer tomography, and PET/MR is increasing. The radiologist has in depth expertise within imaging technology, performance of studies, and diagnostic abilities of imaging techniques. A program directed towards developing imagers towards translational imaging research will include in-depth education and training in lung physiology, pulmonary disease mechanisms, multimodality imaging bridging CT, PET/CT, MR and PET/MR, and the molecular techniques. With such knowledge and training, radiologists will be prepared to serve as principal investigators and collaborators in multidisciplinary teams. An understanding of imaging technologies and their capabilities, the clinical challenges, and molecular techniques will enable imagers to provide innovative solutions to diagnostic dilemmas in pulmonary and cardiovascular disease.

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

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Goal 3: Advance Translational Research

Calcium channels in cardiovascular functions and diseases

Fifty years ago Prof. Harald Reuter of the University of Bern, Switzerland obtained the first experimentally supported evidence that the calcium channel is a physiologically distinct entity. Further stimulated by the synthesis of the dihydropyridine calcium channel blocker nifedipine, the field of calcium channel research rapidly encompassed cardiovascular and other powerful biomedical directions.

Submitted by (@soldatovn.humgenex)

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 coming Theme Issue of Current Molecular Pharmacology "50th Anniversary of Calcium Channel Research: Biomedical Perspectives" brings together leading experts in calcium channel research with the aim of discussing new ideas and recent developments in research of voltage gated calcium channels and calcium signaling with specific focus on biomedical perspectives. This CMP Theme issue may be particularly interesting for those who are involved in molecular cardiovascular research. Please see further: http://benthamscience.com/journal/upcoming-articles.php?journalID=cmp

Feasibility and challenges of addressing this CQ or CC :

In 2010, heart diseases cost the United States $316.4 billion in health care services, medications, and lost productivity (Circulation 2010, 121, e1). Search for new therapeutical targets associated with the family of calcium channels becomes an increasingly powerful future direction.

Name of idea submitter and other team members who worked on this idea : Nikolai M. Soldatov, Ph.D., Guest Editor, and authors of 23 papers of the CMP Theme Issue

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Goal 1: Promote Human Health

Environmental stimuli and the lung: predictors of homeostatic or pathological responses

What are the molecular and cellular responses in the lung that occur after environmental stimuli that predict homeostatic resilience or transition to disease, disorder, or aging?

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 :

Addressing this line of research could define biomarkers and pathways useful for prediction of how human response to an external stimulus of varied nature (i.e. microorganism, chemical, physical) could lead to specific outcomes in relationship to the duration of the exposure and the genetic makeup of the individual exposed. Identification of early signals and the pathways involved could lead to novel preventative or therapeutic approaches.

Feasibility and challenges of addressing this CQ or CC :

Methods for systems biology approaches to address complex pathobiological iterations are ready to be exploited to answer these questions.

Great progress has been made in the clarification of basic mechanisms of molecular and cellular response to environmental stimuli, in cross-sectional analyses. The continuum of the response in relationship to the genetic background of individuals responding with a homeostatic or pathological long-term outcome is missing from these data.

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

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Goal 2: Reduce Human Disease

Detection of rupture prone small aortic aneurysms

Critical challenges in the assessment of aortic aneurysms are: (1) Availability of reliable animal models that simulate the human pathology, (2) Availability of molecular imaging resources – identification of biomarkers, development of targeted imaging probes and pre-clinical imaging methods, and plasma markers that predict whether an aneurysm is prone to rupture or dissection, (3) Bringing together a wide array of multi-disciplinary ...more »

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 :

Developing clinically viable methods to detect rupture prone aneurysms can lead to better methods of diagnosis and intervention and avoid preventable fatalities

Feasibility and challenges of addressing this CQ or CC :

Several other disease areas including oncological that had similar gap was filled by NIH (NCI) and the challenges were overcome in less than 10 years. The scientific expertise to fill the gap exists, however they work in silos, which need to be brought together to fulfil this gap and is achievable in less than 10 years

Assessment of aortic aneurysms that are prone to rupture or dissection has been an elusive target. Current clinical practice measures the aortic diameter and fails to relate to the pathophysiology and biomechanical properties of the aneurysm in deciding preventive surgery. Critical gap exists in the diagnosis of aneurysm especially with small aneurysms (3 - 5 cm in diameter) that are rupture prone. Based on autopsy about 10 percent of individuals with small abdominal aneurysms had undergone fatal rupture, while 40 percent with diameters of 7-10 cm had intact aneurysm and died from other causes. International Registry of Aortic Dissection found that 40% of thoracic aneurysms dissected at diameters smaller than 5 cm.

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

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Goal 2: Reduce Human Disease

Molecular determinants of pulmonary failure in sepsis

Respiratory failure in sepsis is almost universal and leads to worse clinical outcomes, yet it is poorly understood. Recent epidemics of pulmonary failure from respiratory viruses (e.g. influenza, SARS, MERS, etc) makes understanding molecular determinants of respiratory failure and the associated inflammatory and physiologic responses, critical for improving the health of our nation and potentially mitigating future ...more »

Submitted by (@greg.martin)

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

Details on the impact of addressing this CQ or CC :

Exploring and understanding the molecular determinants of pulmonary failure will impact not only the predictable complications of acute respiratory illnesses such as influenza, but also inform our understanidng and treatment of myriad other common respiratory illnesses resulting in pulmonary failure, such as pneumonia, chronic obstructive pulmonary disease, asthma, obesity hypoventilation, etc.

Feasibility and challenges of addressing this CQ or CC :

Patients receiving critical care services in the United States are among the most close monitored, including continuous monitoring of cardiorespiratory physiology. This highly monitored population is a nature source for studying longitudinal changes in molecular patterns and respiratory physiology.

Name of idea submitter and other team members who worked on this idea : Society of Critical Care Medicine Executive Committee/Council

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Goal 2: Reduce Human Disease

Quantitative imaging biomarkers for chronic lung disease

Critical Challenge

Submitted by (@str0001)

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

Details on the impact of addressing this CQ or CC :

Methods for stratifying patients with diffuse lung disease are crucial for predicting their clinical course and directing appropriate therapies accordingly. Currently imaging markers for prognostic stratification are limited, due to observer variability in characterizing the type and degree of computed tomography (CT) abnormalities. A reproducible method for categorizing varying diffuse lung diseases on CT imaging is needed, particularly in combination with other biomarkers in a multidisciplinary approach. With lung cancer screening, the characterization and stratification of patients with varying COPD phenotypes and interstitial lung disease are essential to aid in management of the large number of patients who currently satisfy criteria for CT lung cancer screening.

Feasibility and challenges of addressing this CQ or CC :

Currently the classification of diffuse lung disease on CT is based upon visual evaluation and qualitative or semi-quantitative evaluation of CT data. Diffuse lung disease manifests with varying CT findings and distribution within the lung. Computer-assisted tools for quantifying airways and parenchymal disease have been developed. More-sophisticated quantitative computer image-analysis methods, such as those that address three-dimensional spatial orientation, are possible given advances in computer capabilities yet remain in need of further development. Advances in magnetic resonance imaging (MR) technology, positron emission tomography (PET), and PET/MR will increase the ability to characterize diffuse lung disease quantitatively. The ability of such technology to differentiate subtypes within more frequently occurring and clinically-significant diffuse lung disease is feasible. Such tools would impact a large population, particularly given the potential need to phenotype emphysema and smoking-related interstitial pneumonias in those undergoing CT screening.

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

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Goal 2: Reduce Human Disease

Molecular basis for cardiac and neurological damage after cardiac arrest

What is the sequence and time course of molecular events that cause irreversible cardiovascular and neurologic dysfunction during and after cardiac arrest?

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 1: Promote Human Health

Environmental Exposures and Atopic Disease

As the current chair of the Research and Training Division, I would like to convey that the AAAAI membership would like the NHLBI to consider the following in the development of its strategic plan:

 

What are the molecular and cellular responses in the lung that occur after environmental stimuli (including allergens) that predict homeostatic resilience or transition to atopic diseases?

Submitted by (@wheeze)

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 : Mitchell Grayson on behalf of the American Academy of Allergy, Asthma, and Immunology

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Goal 3: Advance Translational Research

Developing Curative Approaches to Cardiovascular Disease rather than Chronic Magement

Most Pharmacological interventions in cardiovascular diseases tend to address to be used in palliative manner and chronically. There is urgent need for treatments that are curative. This goes to identifying molecular drivers of the diseases and targeting them to correct the underlying pathophysiology rather than symptom suppression.

Submitted by (@john.buolamwini)

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

Details on the impact of addressing this CQ or CC :

True conquer of cardiovascular diseases, and reversing the chronic nature of these diseases.

Feasibility and challenges of addressing this CQ or CC :

Possible but challenging requiring a highly multidisciplinary approach and collaboration.

Name of idea submitter and other team members who worked on this idea : John. K. Buolamwini

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