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.

Goal 2: Reduce Human Disease

Rare Lung Diseases/Sarcoidosis

To investigate the effects of antimycobacterial therapy on pulmonary and extrapulmonary immune response and granulomatous disease.

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 :

As you know, sarcoidosis is a granulomatous disease of unknown etiology, characterized by disparate clinical outcomes. Its pathogenesis is a multifactorial process, characterized by dysregulation of T lymphocyte function and Th-1 cytokine expression. Systemic defects in IL-2 and IFNy expression in sarcoidosis have been well-described" 2 Reductions in the cytokine IL-2 and its mediator, lymphocyte-specific protein tyrosine kinase (p56Lck), correlate with disease severity", Also, CD4+ and CD8+ T cells, as well as B cell lymphopenia is associated with disease severity", These observations are particularly important because loss of adaptive immunity and reduced Lck expression has been associated with disease progression among granulomatous disease.

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

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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 »

Submitted by (@lakshmanankrishnamurti)

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 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

Clinical Trials in Pediatric Sleep Disorders - Effect of adenotonsillectomy

Effect of adenotonsillectomy on behavioral and cardiovascular outcomes in children with primary snoring

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 :

The recent NHLBI Childhood Adenotonsillectomy (CHAT) study showed highly significant behavioral improvements in children with obstructive sleep apnea syndrome . This study included children with an apnea hypopnea index as low as 2/hr. Many small or suboptimally controlled studies suggest that even primary snoring can affect behavior. If large randomized controlled trials confirm this finding, it will radically affect the treatment of the estimated 10% of children who snore.

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

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Goal 2: Reduce Human Disease

Effect of early mobilization

Does early mobilization, i.e. as soon as mechanical ventilation begins, improve long term outcomes in ALI survivors??

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 : American Thoracic Society member

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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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Goal 2: Reduce Human Disease

Development of Optimally Hemostatic, Systemically Safe, Platelet Mimetics or Substitutes

What are the knowledge and technological gaps in production, evaluation and clinical translation of donor-independent platelets for transfusions? Specific questions include: a) How can stem or progenitor cells be expanded to maximize platelet production?; b) What are the hemostatically relevant design and function requirements and evaluation metrics for ideal/optimal “biologic” and “synthetic” platelets? c) What preclinical ...more »

Submitted by (@dtriulzi)

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

Details on the impact of addressing this CQ or CC :

Platelets produced from induced pluripotent stem or progenitor (megakaryocyte) cells (biologic production), as well as, manufactured from engineered biomaterials (synthetic production) could address clinical needs of supply issues and transfusion related function and safety concerns. However, there are key knowledge and technology gaps in both approaches, and in corresponding qualitative and quantitative correlation of the platelet products with hemostatic efficacy and safety. One important step is increasing both stem and progenitor cell expansion in culture. A parallel step is to develop synthetic platelet mimetics using biomaterials engineering. Finally, the hemostatic efficacy and safety of the products need to be established in clinically relevant models and patients.

Feasibility and challenges of addressing this CQ or CC :

The above questions can be addressed by establishing high throughput screens for compounds that expand CD34 or CD41 cells or trigger platelet release and ploidy, developing culture methods using 3D scaffolds to mimic bone marrow perivascular niche, using proteomics or RNA-sequencing to reveal molecules critical for terminal megakaryocyte maturation and platelet formation. Large-scale bioreactors can be adapted to test molecules, triggers and conditions for amplifying platelet production. For synthetic platelet mimics, the benefits of integrating natural platelet’s physico-mechanical properties with its hemostatic biochemical properties on synthetic biomaterial platforms, can be studied in vitro. Scaled-up particle fabrication technologies with control over particle geometries and surface chemistries, can be adapted for manufacturing synthetic platelets. Large-scale production of platelets through biologic and synthetic routes would enable studies in animal models with clinically relevant bleeding disorders, to correlate design and dosage with hemostatic function and safety. Subsequently, clinical studies can be carried out in Phase 1 for safety analysis in dose escalation and in vivo kinetics (recovery and survival for biologic, degradation and clearance for synthetic). Phase II studies can evaluate bleeding incidence, transfusion requirements and thrombotic events in a controlled population of thrombocytopenic patients under-doing chemotherapy or stem cell transplantation.

Name of idea submitter and other team members who worked on this idea : NHLBI 2015 State of the Science in Transfusion Medicine

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Goal 2: Reduce Human Disease

Combination Iron Chelator Trials in Thalassemia and other transfusion-dependent anemias

Three chelators are presently available in the US and much of the world: parenteral deferoxamine, and oral deferasirox, as well as oral deferiprone. Monotherapy is unsuccessful in a significant minority of patients, due to side effects or inadequate response at tolerable doses. Taking a page from enormously successful strategies for combination oral therapy in hypertension, led by NHLBI and others over the past four ...more »

Submitted by (@gcioffi)

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

Feasibility and challenges of addressing this CQ or CC :

NHLBI should lead the way for these trials, which will be of enormous benefit to reduce morbidity and mortality in thalassemia, a terribly common problem worldwide, as well as in the rare, transfusion-dependent congenital anemia.

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Goal 2: Reduce Human Disease

Repair and Regenerate the Kidney

Chronic Kidney Disease (CKD) affects millions in the US, and is one of the new diseases on the rise globally. New therapies to slow CKD and to repair and regenerate failing kidneys are drastically needed to reduce health care costs and improve lives.

Submitted by (@ceci00)

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

Details on the impact of addressing this CQ or CC :

New therapies to slow CKD and to repair and regenerate failing kidneys are sorely needed to reduce health care costs and improve lives.

Feasibility and challenges of addressing this CQ or CC :

Our understanding of renal function and risk factors is greater than ever. Our ability to diagnose is technologically advanced. We now need to increase efforts to identify therapeutic targets and develop regenerative approaches to prevent and treat CKD.

Name of idea submitter and other team members who worked on this idea : Ceci Giachelli

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Goal 2: Reduce Human Disease

Acetaminophen and asthma

Prospective studies on acetaminophen and asthma - randomized/controlled/adequately powered - use in pregnancy and asthma development in utero, use in early childhood

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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Goal 2: Reduce Human Disease

Clinical Trials in Pediatric Sleep Disorders - Effect of adenotonsillectomy

Effect of adenotonsillectomy on neurocognitive and behavioral outcomes in infants and and toddlers with obstructive sleep apnea syndrome.

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 :

The CHAT study showed few significant changes in cognitive outcomes in school-aged children with OSAS. However, these children (aged 5-9 years) may have suffered from OSAS too long to allow for reversibility of central nervous system damage. The peak prevalence of OSAS occurs in much younger children. Theoretically, these children are much more likely to show cognitive improvement after treatment, due to a shorter duration of OSAS (with its resultant hypoxemic damage) and increased plasticity of their nervous system. These young children are often not treated, due to either underdiagnosis or concern about the increased risks of adenotonsillectomy in very young children. Thus, if it is found that early treatment reverses cognitive damage, the clinical management of these children would be profoundly affected.

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

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Goal 2: Reduce Human Disease

Early COPD

What does early COPD actually look like. This is defined as severe COPD 30 years prior to its manifestation.

Submitted by (@davidmannino)

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

Details on the impact of addressing this CQ or CC :

Prevention programs in COPD either target smoking or those with established disease. Better understanding the factors that lead to the development of COPD (both in ever and never smokers) is critical to improved disease prevention.

Feasibility and challenges of addressing this CQ or CC :

We need to revisit long term studies in novel ways- and look at new cohorts. Better biomarkers need to be developed.

Name of idea submitter and other team members who worked on this idea : Dave Mannino

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Goal 2: Reduce Human Disease

Promotion of human health and reduction of human disease

Congenital heart disease (CHD) is the most common birth defect and leading cause of defect-related infant mortality. With nearly 1 in 100 babies born annually with CHD, the needs of children and adults born with CHD are ongoing and costly. More focused research into CHD promotes human health and will result in a better quality of life, reduced premature death and lower healthcare costs.

Submitted by (@dstephens)

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

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