Goal 2: Reduce Human Disease

Role of epigenetic mechanisms in cardiovascular disease

Are epigenetic changes the cause or the consequence of changes in cell function that contribute to cardiovascular disease?

If they are the cause, what are the mechanisms that lead to changes and how do they impact disease pathogenesis?

If the consequence, do they play any role in disease pathogenesis?

What methods can be used to test if epigenetic changes play a causal role in disease pathogenesis? Thus far studies... more »

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

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Although it is widely speculated that epigenetic control mechanisms play a critical role in disease pathogenesis, few if any studies, particularly in the CV field, have actually determined if and how epigenetic mechanisms result in functional changes in the plethora of cells that contribute to CV disease pathology. Moreover, there is a general lack of methods available to determine how specific epigenetic modifications, including histone modifications or DNA methylation of a given gene locus impacts gene expression and function of that cell. Rather, most studies have been limited to studying the effects of global alterations in chromatin structure, and/or studying global changes in epigenetic modifications average over the tens or hundreds of cell types and phenotypes within a complex tissue.

We must develop approaches to dissect the causal role of specific epigenetic modifications in controlling cell function in health and disease.

Feasibility and challenges of addressing this CQ or CC

There are approaches evolving that enable one to do epigenomic edting in single cells but thus far they have not been done in the CV system, nor in vivo. They are feasible but will take a major investment to be successful.

Keep in mind that epigenetic mechanisms presumably regulate overall change in cell function as a consequence of exposure to disease promoting stimuli. Importantly, this is in response not only to the environmental milieu to which the cell is currently exposed, but an integral of past signals it and its predecessors experienced. Unlocking these control mechanisms will likely greatly advance our understanding of all disease processes, but particularly CV diseases which typically develop over years or decades.

Name of idea submitter and other team members who worked on this idea Gary K Owens

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Goal 2: Reduce Human Disease

What is the place of curative therapies in the management of Sickle Cell Disease

Advances in the care of pediatric patients with sickle cell disease ( SCD) have resulted in improved survival to adulthood.However, adulthood is marked by rapid disease progression, impaired quality of life and premature mortality. Hematopoietic cell transplantation(HCT) from matched sibling donor has curative potential, but has been offered mainly to children. Refinements in the conditioning regimen, supportive care,... more »

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

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To overcome this obstacle to progress in the field, we propose the creation of the funding mechanisms for a multicenter clinical trial consortium which would bring together investigators in field and facilitate study the outcomes of CT for patients with different types of donors and stem cell sources and compare them to outcomes in phenotypically matched controls receiving best available standard of care.Answering the compelling question about the role of CT in the management of SCD has the potential to have a catalytic effect in progress in this field. Patients are are then more likely to receive CT or standard of care at the appropriate time and in the manner in which they are most likely to have a positive outcome. This has the potential to reduce morbidity and premature mortality and in the long run, to decrease the burden of the disease on the healthcare system. The advent of clinical trials of gene therapies for SCD offers the prospect of even greater applicability of curative therapies. Thus, a consortium developed to answer this CQ would serve as a crucial vehicle for providing access to a greater proportion of patient to these personalized curative therapies . Such studies would also be powered to answer the question about who should receive the curative therapy, when they should receive it, and how it would impact their SCD related complications, late effects, survival and quality of life and help families make informed choice appropriate for their situation.

Feasibility and challenges of addressing this CQ or CC

The increasing applicability and acceptability of HCT for SCD is evidenced by the doubling in the number of such procedures reported to CIBMTR in the decade starting 2001. Refinements in conditioning regimen and supportive care continue to improve outcomes in children and now in adults with SCD undergoing HCT from HLA matched related donors. Recently, HCT from unrelated donors and from haplo-identical donors have further increased the applicability of HCT. Opening of gene therapy trials has further raised the prospect of cure for a greater proportion of patients. These developments are evidence of the feasibility of recruitment to large multi-center comparative trials of SCD and standard of care. Recently, there has been increasing collaboration among investigators in the field with informal consortia being developed by investigators coming together to study HCT for children, adults or HCT from haplo-identical donors. These groups are also increasingly working with SCD hematologists, families and other stakeholders. There is also increasing cross-cutting collaborations with other medical specialists and behavioral and translational scientists Thus, the convergence of several factors described above suggests that the time is fortuitous for a major initiative from the NHLBI to bring investigators together and create the infrastructure that will enable these investigators to seek definitive answers to the challenging question “What is the place of curative therapy in SCD?”.

Name of idea submitter and other team members who worked on this idea Lakshmanan Krishnamurti, MD, Allistair Abraham MD, John Horan MD and members of the Sickle cell Transplantation and Research Alliance

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Goal 2: Reduce Human Disease

Why is the heart resistant to cancer?

Cancer of the heart is almost unheard of, whereas most other organs can develop cancer. Why is this?

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

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If we could understand why cancer does not develop in the heart, this might help to develop strategies to protect other organs from doing so.

Feasibility and challenges of addressing this CQ or CC

To my knowledge, no one has looked at this problem, because cardiologists and oncologists train in different fields. With molecular profiling, iPS technology, and animal models, this question can be addressed.

Name of idea submitter and other team members who worked on this idea Henry Chang, M.D.

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Goal 2: Reduce Human Disease

Exercise effects on cellular level

What cellular and/or intracellular signaling events are activated in response to acute or chronic physical activity that lead to or explain improvements in health outcomes, prevention, or treatment of lung diseases?

Which metabolic signatures induced by exercise/physical activity would be predictive/ associated with poor lung disease prognosis?

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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Goal 2: Reduce Human Disease

Reducing the toxicity and morbidity of blood transfusions

Transfusion is the most commonly prescribed inpatient procedure. Blood transfusions have been shown in randomized trials to predispose to novel side effects. These include nosocomial infection, multi-organ failure, thrombosis and mortality due to these causes. Even in an era of more restrictive transfusion, there is an urgent need to understand and mitigate the mechanism(s) of these effects. Some patients will always... more »

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

Details on the impact of addressing this CQ or CC

Blood transfusion probably accounts for thousands or tens of thousands of unnecessary deaths each year due to side effects. Morbidity, including nosocomial infections, probably involves tens or hundreds of thousands of patients, for one example. Thus understanding the mechanisms of transfusion toxicity, and developing effective strategies for mitigating these undesirable effects is the critical question for this widely employed therapy.

Feasibility and challenges of addressing this CQ or CC

Preliminary data suggests that in addition to universal leukoreduction (not yet adopted in the USA), strategies such as washing, nitric oxide replenishment, rejuvenation and novel preservative solutions may be able to mitigate some of the effects of allogeneic blood transfusions. There are many fruitful lines of investigation that have recently come to the fore, such as a recognition that red cell transfusion is toxic in part because of the load of free iron, heme and hemoglobin that is part of every stored red cell transfusion.

Name of idea submitter and other team members who worked on this idea Joanna M. Heal MBBS MRCP; Majed A. Refaai MD

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Goal 2: Reduce Human Disease

Patient Registries

Researchers at academic institutions, research foundations, and industry are poorly managing clinical data about patients they treat and enroll in clinical trials. A better coordinated patient registry effort related to heart, lung, and blood disease patients would yield long term benefits for clinical research and clinical care improvement.

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 Cystic Fibrosis Foundation

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Goal 2: Reduce Human Disease

Determining the significance of variants of unknown significance

Variants of unknown significance (VUS) confound the value of genetic testing. We need to improve our understanding of the clinical significance of VUS so we can more definitively re-classify them as pathologic or benign variants.

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

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Next gen sequencing and clinical genetic testing are becoming a more frequent component of clinical care. Not infrequently a VUS result is returned providing little clinical value to the patient. Determining the significance of these variants will be extremely valuable to patients undergoing genetic testing.

Feasibility and challenges of addressing this CQ or CC

Bioinformatics and big data infrastructure will mature over the next several years to allow us to record VUS results, follow patients longitudinally, aggregate data, and ultimately determine the significance of VUS.

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

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Goal 2: Reduce Human Disease

Kinetic analysis of transcriptional regulation by aberrant transcription factors in vivo

Aberrant transcription factors, such as leukemia fusion proteins, promote diseases by deregulating transcription of target genes. Recent genome-wide studies have provided new insight into transcriptional deregulation by aberrant transcription factors. Most of these studies have not used cells with synchronized transcriptional activities at specific repression/activation steps and, therefore, may have limited value in... more »

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

Feasibility and challenges of addressing this CQ or CC

These studies are feasible. Transcriptional regulation of a population of cells may be synchronized by epigenetic drugs, or by using inducible expression/knockdown approaches. Alternatively, it may be possible to overcome the heterogeneity issue by single-cell-based analysis. Next, time-dependent genome-wide studies may be applied to the cells to reconstruct dynamic transcriptional pathways associated with aberrant transcription factors. These approaches may be generally applicable to the study of other disease-related transcriptional and signaling molecules.

Name of idea submitter and other team members who worked on this idea Jinsong Zhang

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Goal 2: Reduce Human Disease

Long-term pulmonary function in survivors of critical illness

Pulmonary function is known to suffer during the early recovery phases from critical illness, but the long-term patterns of recovery and associated consequences are uncertain. In addition, the clinical and molecular determinants of progressive deterioration or recovery of pulmonary function remain unknown.

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 Society of Critical Care Medicine Executive Committee/Council

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Goal 2: Reduce Human Disease

Integrating palliative care into the care of patients with heart, lung, and blood disease

How can we best integrate primary and specialty palliative care into the care of patients with serious heart, lung, and blood diseases?

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

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There is increasing awareness of the importance of palliative care in the care of patients with serious illness. Palliative care focuses on improving quality of life and reducing the stress of a serious illness for patients and their families and can be provided together with curative or life-prolonging treatments. It includes both primary palliative care (delivered by all cliniicans who care for patients with serious illness) and specialty palliative care (delivered by physicians, nurses, social workers, chaplains and others with special training in palliative care.) Patients with serious heart, lung, and blood diseases have profound unmet palliative care needs and it is not clear how these needs can best be met.

Feasibility and challenges of addressing this CQ or CC

Studies show dramatic benefit of integrating palliative care into the care of patients with cancer, but there is little data on the best way to improve palliative care for patients with serious heart, lung, and blood disease. The opportunity exists to support research that develops and evaluates interventions to improve primary and specialty palliative care for patients with heart, lung, and blood diseases.

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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.

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

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Goal 2: Reduce Human Disease

Single nucleotide polymorphisms, microarray and sickle cell disease

Do SNPs account for any of the variability seen in the phenotypic expression of sickle cell disease? Can microarray analysis be used to map these SNPs, promoting refined care plans for those living with sickle cell disease?

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

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Multiple Single Nucleotide Polymorphisms (SNPs) have previously been identified in the mu opioid receptor and it is estimated that millions might exist throughout the genome. Drastic phenotypic variability exists among patients in the sickle cell community. Do SNPs account for any of this variability and can this information be used to more effectively treat sickle cell disease.

Name of idea submitter and other team members who worked on this idea Sickle Cell Warriors, Inc. community members

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Goal 2: Reduce Human Disease

Life-Course Approach to Science

We encourage the NHLBI to include research focused on children as a priority in their strategic vision. We encourage them to consider the implications of a life-course approach, where childhood presents a unique opportunity to set the trajectory for health risk as an adult. This also implies that interventions targeting children may have the greatest impact on the population as a whole in the long term.

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 Society of Pediatric Nephrology (ASPN)

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Goal 2: Reduce Human Disease

Sleep Apnea

The general area is that of preoperative risk management of sleep apnea patients undergoing major surgery. This field is burgeoning with clinical activity. A large amount of healthcare dollars are expended annually in order to detect sleep apnea and offer therapy that is of unproven value. Most all of the data is retrospective case series or a mixture of retrospective and prospective cohort studies. Yet, across the country,... more »

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

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The existing data shows that sleep apnea may be moderate risk factor for poor outcomes and complications from surgery but the magnitude of the risk and the degree to which sleep apnea therapy modifies this risk is not known and won’t be determined without larger scale trials. This field desperately needs some randomized trials to answer some of these questions. Trials which randomize patients undergoing some major surgery to a sleep apnea treatment with CPAP if OSA is diagnosed before surgery  vs. treating with CPAP after surgery in the post operative period is one such study that could be performed.

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

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