Goal 2: Reduce Human Disease

To extend our knowledge of the pathobiology of heart, lung, blood, and sleep disorders and enable clinical investigations that advance the prediction, prevention, preemption, treatment, and cures of human disease.

Strategic Goal: Goal 2: Reduce Human Disease

Further development and clinical usefulness of COPD phenotypes

Further development and clinical usefulness of COPD phenotypes

a. Linking phenotypes to clinically meaningful outcomes

b. Establishing treatment algorithms for different phenotypes

Submitted by (@nhlbiforumadministrator)

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

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

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Strategic Goal: Goal 2: Reduce Human Disease

Improving understanding of heart attack mechanisms in women and targeting of treatment

There remain many differences between women and men in the risk of myocardial infarction (MI or “heart attack”), manifestations of MI and outcomes after MI. The time in which the facts about differences between the sexes were unknown or ignored has passed. However, there are many basic answers women and their physicians need, such as: a) Why are younger women with MI at such high risk of death as compared to their male ...more »

Submitted by (@harmony.reynolds)

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 sex differences is the most fundamental aspect of personalized medicine. When considering MI, some sex differences, such as lower risk of MI and a lesser extent of coronary artery disease (CAD, plaque buildup), favor women. Others, such as the 2-fold higher risk of death in younger women with MI and sex differences in the association between diabetes and MI, favor men. Insights into these and other sex differences should provide the foundation for optimal treatment for the prevention of MI and its complications.

Feasibility and challenges of addressing this CQ or CC :

Mechanistic and descriptive studies may be needed before clinical trials can be undertaken.

Name of idea submitter and other team members who worked on this idea : Harmony Reynolds

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Strategic Goal: Goal 2: Reduce Human Disease

The relationship between genetic variation and disease mechanisms

What is the contribution of individual differences in RNA processing to disease causation, disease modification, disease susceptibility, and positive or negative responses to therapies? Studies using genome sequencing combined with RNA-seq have determined that genetic variation affects regulation of RNA processing as frequently as transcriptional regulation. While transcriptional networks are well defined in heart development ...more »

Submitted by (@tcooper)

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

Details on the impact of addressing this CQ or CC :

There are two areas of impact. First is to develop a better understanding between the effect of genetic variation on RNA processing and how individual differences in RNA processing translate into "phenotype" such as disease causation, disease modification, disease susceptibility, and positive or negative responses to therapies. Genes are filled with cis acting elements that are required for specific patterns of RNA processing. Variation that affects these cis elements are now known to produce different splice variants or mRNAs with different stabilities between individuals. This mechanism translating genotype to phenotype has not been explored. Second is to understand the RNA processing networks as well as we understand transcriptional networks during heart development and in heart disease. This understanding is very likely to provide previously unknown therapeutic approaches and targets.

Feasibility and challenges of addressing this CQ or CC :

The high through put approaches available to compare genome and transcriptome sequences,computational approaches to predict the cis elements for RNA processing, high throughput analysis for RNA binding proteins and RNA structure have provided the tools necessary to perform genome-transcriptome comparisons as a starting point. Current exome/genome analysis ignores the influence of genetic variation in RNA processing. The tools are available. The first challenge is to decide on the question and there are two areas: One- what is the role of RNA processing in heart disease/how can RNA processing be used as a therapeutic target and Two - how much does differences in RNA processing (in addition to transcription) contribute to individual phenotypic differences relevant to disease?

Name of idea submitter and other team members who worked on this idea : Tom Cooper

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Strategic Goal: Goal 2: Reduce Human Disease

Environmental induction of congenital heart defects and finding means of prevention

Congenital heart defects (CHDs) continue to be the leading cause of death among all infants with birth defects. It is reported that approximately 10% of cardiac congenital anomalies have a genetic basis. An equal percentage, or ~10%, is due to environmental factors. For ~60% the etiology is unknown and considered to have a multifactorial basis, eg, environmental agents having a role against a specific genetic background, ...more »

Submitted by (@kerstilinask)

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

Details on the impact of addressing this CQ or CC :

College drinking is up especially among young women. Women of both high and low income levels drink, may be smoking marijuana, or are exposed to other environmental toxicants. Are there gender effects, as it has been reported that in the US, more male babies undergo severe cardiac surgeries than female. Few grants are presently funded that take a teratological approach to understanding mechanisms underlying induction of congenital heart defects that can occur before a women realizes being pregnant. The embryo may already have been harmed by then and the effects last a lifetime for the child. High dose folate may be preventative of CHDs and this needs to be better defined and the effects of high folate doses on the adult and fetus need to be analyzed. A possible role for gender should be defined.

Feasibility and challenges of addressing this CQ or CC :

A recommended goal is to emphasize the submission of grants specifically addressing the etiology of congenital heart defects due to environmental factors and their prevention, using cell and molecular teratological approaches. Reinstate a study section on Teratology and Toxicology of Birth Defects made up of PIs working in those fields. There used to be four such study sections and were all removed years back. One such section should be reinstated. Current study sections lack such individuals on the panels due to this area receiving little funding. The neural field is way ahead in funding this topic and as a result the heart tends not to be mentioned in available literature that is provided to women of child-bearing age. Yet the risk for heart anomalies is equally as high and important as are effects on neural development. Similarly, both have lifelong consequences for the individual physically and psychologically and in cost to society with repeating hospitalizations and surgeries. Effects on the heart may be so severe that death occurs already in utero and may not always be counted among the epidemiological studies.

Name of idea submitter and other team members who worked on this idea : Kersti K. Linask, PhD

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Strategic Goal: Goal 2: Reduce Human Disease

Neuroendocrine system in heart and lung disease

What is the role of the non-neuronal neuroendocrine system in lung and heart pathophysiological processes, and can it be targeted for lung diseases therapies?

Submitted by (@nhlbiforumadministrator)

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 : NHLBI Staff

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Strategic Goal: Goal 2: Reduce Human Disease

Do we yet know all of the Resident Cellular Components of the Human Lung?

The DLD, NHLBI workshops conducted and published (Reference 1, 2, 3) had as their purpose to stimulate research that would identify still obscure or novel cellular components of the human lung to determine cell function in promoting respiratory tract development and in health that contributes to disease, so that better therapy might result. With robust technologies now available, especially genomic advances, how much ...more »

Submitted by (@nhlbiforumadministrator1)

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

Details on the impact of addressing this CQ or CC :

To completely understand how the human lung responds and reacts to inhaled or aspirated particles, microbes, and environmental antigens, etc.; then initiates innate and/or acquired adaptive immunity; or creates a milieu wherein cancerous cells that have travelled to the lung can establish metastatic sites, we must identify, characterize through special phenotyping and cellular function, and isolate for ex vivo study the still understudied and unknown properties of a sizable number of the 40 resident cell types in the human lung.

 

Knowledge about all the resident cells in the human lung and their functions should enhance understanding of the respiratory tract in health and disease.

 

References:

1. Needs and opportunities for research in hypersensitivity pneumonitis.

Fink JN, et. al.

Am J Respir Crit Care Med. 2005 April 1;171(7):792-8. Review.

 

2. The mysterious pulmonary brush cell: a cell in search of a function.

Reid L, et. al.

Am J Respir Crit Care Med. 2005 July 1;172(7):136-9. Review.

3. Resident cellular components of the human lung: current knowledge and goals for research on cell phenotyping and function.

Franks TJ, et. al.

Proc Am Thorac Soc. 2008 Sep 15;5(7):763-6. Doi: 10.1513/pats.200803-025HR.

Feasibility and challenges of addressing this CQ or CC :

Technologies seem available.

Name of idea submitter and other team members who worked on this idea : Herbert Y. Reynolds, M.D.

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Strategic Goal: Goal 2: Reduce Human Disease

New Clinical Research Methodologies for Rare Diseases

What innovative methodologies applicable to small cohorts and rare outcomes can better ensure the success of clinical and implementation studies in the rare diseases affecting heart, lung, blood, and sleep?

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 :

Efficient translation of clinical observation into discovery science, and, particularly, the timely translation of potential therapeutic target identification into the treatment of rare diseases has been impeded by the reality that rare disease populations are often too small to be studied using “classical” epidemiology, clinical trial, and implementation science methodology. Overcoming these barriers will require both the adaptation of current clinical research methods and the development of novel methodologies. The requirement for better methods in rare disease clinical science will become even more urgent with time as systems biology more specifically defines and sub-characterizes ‘common’ heart, lung, blood, and sleep disease populations

Feasibility and challenges of addressing this CQ or CC :

This problem has been recently addressed through special initiatives in the application of small trial methodology into the planning and design of clinical trials in rare hemostatic disorders and sickle cell disease. Furthermore, small clinical trial methodologists have begun to populate the CTSAs and Regulatory Agencies. Their expertise in clinical trial design and biostatistical methods, and their creative ideas can be brought to bear in the clinical trials required to advance NHLBI scientific priorities.

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

Define the biological basis, new diagnostics and therapeutics for severe sarcoidosis phenotypes

Sarcoidosis affects individuals of all races and ages and both genders, although it tends to cause significant morbidity and mortality for people in the prime of their productive life. Women, minorities and underserved populations tend to be more affected. Recent studies suggest that sarcoidosis and its severe manifestations, such as cardiac, neurologic and end stage pulmonary disease' are increasing, While the current ...more »

Submitted by (@maierl)

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

Details on the impact of addressing this CQ or CC :

Increasing our understanding of the biological basis of sarcoidosis, its more severe phenotypes, and resolution of disease, will help improve detection and personalized management and treatment of this disease, ultimately reducing disease burden. With the current availability of epidemiologic, genetic, genomic and epigenetic tools and studies, as well as buy in from sarcoidosis patient groups, we are poised to address why some people develop more severe forms of this disease. While genetic variants are associated with sarcoidosis, the specific variants responsible for disease risk and that dictate disease activity are largely unknown. The results of studies to date suggest that other susceptibility factors or forms of genetic regulation must act in concert with exposure in the development of sarcoidosis. Growing data in other immune-mediated diseases suggests that epigenetic mechanisms in combination with genetic susceptibility and environment may help explain disease risk. By understanding these genetic, genomic and epigenetic factors, and better defining the natural history of sarcoidosis, interventions can be tested and undertaken to potentially prevent or treat the development and or progression of this devastating disease.

Feasibility and challenges of addressing this CQ or CC :

The care and management of individuals with sarcoidosis is not well standardized. This has been hampered by a lack of understanding of the natural history, which appears to vary significantly. As a result, undertaking studies to define the pathobiology of this disease is biased based on the centers and researchers involved. There have been few limited multi-center studies of sarcoidosis, except for pharmaceutical trials. In the past few years, NHLBI has funded the GRADS study, a cross-sectional multi-center study, laying the ground work for needed longitudinal multi-center studies of the biological basis of disease. With involvement from a larger sarcoidosis research community and the ability to undertake large scale studies to not only define the epidemiology of this disease, but also the pathobiology of disease based on integrative Omics, new personalized diagnostics and therapeutics can be developed and tested to help address the burden of sarcoidosis.

Name of idea submitter and other team members who worked on this idea : Lisa Maier, Nabeel Hamzeh, Tasha Fingerlin, Ivana Yang, Brian O'Connor, Elliott Crouser

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Strategic Goal: Goal 2: Reduce Human Disease

What is the effect of variant genes on AVM development in HHT

Natural genetic variation between individuals can influence the outcome of carrying an HHT mutation. Some gene variants may be protective while others may increase the risk of AVM or telangiectasis. By identifying the variant genes that alter risk of AVM may give clues to the molecular mechanisms of AVM formation and provide new drug targets

Submitted by (@mariannes.clancy)

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 : Marianne Clancy MPA

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Strategic Goal: Goal 2: Reduce Human Disease

Childhood Interstitial Lung Disease

What is the natural history of the best characterized ChILD disorders (surfactantrelated sequence variants, neuroendocrine cell hyperplasia of infancy (NEHI),pulmonary interstitial glycogenosis (PIG),idiopathic pulmonary hemosiderosis)?

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 :

We know little about the natural history of many of the child entities, and their relative rarity makes it difficult for any one center to answer the major questions they pose. The children has begun a patient registry that will begin to address the issue of natural history and disease tracking.

 

a. To improve the power of such a registry, we suggest that support be provided to find novel methods to link this data base to available electronic medical records of participating centers in order to assess physiologic and other clinical associations with specific diseases.

 

b. Support for a biomarker repository holding serum, frozen and fixed lung tissue, patient DNA, RNA, and proteomic and metabolomic materials, and bronchoalveolar lavage effluent and cell pellets, will allow for genome wide analysis as well as proteomic and metabolomic analysis.

Feasibility and challenges of addressing this CQ or CC :

This question is best addressed in the context of a multicenter data registry, ideally linked to a clinical sample.

Name of idea submitter and other team members who worked on this idea : ATS Member

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Strategic Goal: Goal 2: Reduce Human Disease

Ischemia-independent mechanisms contributing to infarct size

What are the mechanisms of ischemia-independent mechanisms contributing to the infarct size in patients with acute myocardial infarction? Infarct size is the single most important prognostic factor for short- and long-term outcomes. The success in reperfusion strategies have shown that prompt reperfusion leads to a reduction in infarct size, and to improved outcomes. Despite effective reperfusion, however, a secondary ...more »

Submitted by (@aabbate)

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 compelling question may lead to:

1) Improved therapy and outcomes for acute myocardial infarction

2) Reduction of acute morbidity/mortality following reperfusion

3) Prevention of heart failure

Feasibility and challenges of addressing this CQ or CC :

The progresses in basic science/signaling, preclinical models, imaging techniques, and invasive monitoring now provide the ideal setting to complete this research in a preclinical model or pilot exploratory clinical trials.

Name of idea submitter and other team members who worked on this idea : Antonio Abbate

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Strategic Goal: Goal 2: Reduce Human Disease

Biomarkers and phenotypic characteristics of asthma patients

Are there biomarkers or phenotypic characteristics that will allow us to identify the patients with asthma who will experience a more rapid decline in lung function?

Submitted by (@nhlbiforumadministrator)

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

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

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