Goal 2: Reduce Human Disease

Sleep Disorders and Brain Maturation

What is the effect of sleep disorders on child development? Specifically, how sleep apnea with intermittent hypoxia and or sleep deprivation alters the normal trajectory of maturation of brain regions controlling cognition, behavior and the cardiovascular system?

Submitted by (@raouf.amin)

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 significance of the behavioral and cardiovascular findings in children as they relate to health during adulthood is unknown. It remains to be defined whether the behavioral and cardiovascular abnormalities observed in children with sleep apnea are a reflection of structural and functional brain abnormalities, which might persist into adulthood and predispose to health problems at an older age.

A fundamental question that deserve investigation whether brain maturation in children with sleep apnea and sleep deprivation deviate from normal trajectory and whether brain plasticity can restore normal structure and function.

Such knowledge on brain maturation and plasticity in children with sleep disorders could lead to the identification of brain biomarkers that might signal risk for future mood and behavioral disorders and or cardiovascular diseases. The new knowledge will also identify sensitive period(s) during child development for interventions.

Feasibility and challenges of addressing this CQ or CC :

In the last decade, the application of new technologies of fMRI and diffusion MRI have permitted the study of the evolving brain connectome across all stages of development and created new potentials to inform our etiologic understanding of many pediatric and adult diseases.

We now can for the first time examine the brain developmental trajectories in children with chronic medical conditions including sleep disorders and compare the findings to normative data.

Name of idea submitter and other team members who worked on this idea : Raouf Amin, Mark DiFrancesco, Scott Holland

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Goal 2: Reduce Human Disease

Signaling in AVM Developmoent

BMP9 circulates in the blood and signals through the endothelial cell. IN the absence of Alk 1, such as in HHT, the vessels become over-active. The overactivity can be partially balanced by activation of a second signaling pathway: notch. Would targeting notch be a useful drug target to reverse AVM formation

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, Chris Hughes PhD

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Goal 2: Reduce Human Disease

What is the Role of Macrophages in Pathogenesis of HHT

Alk 1 or Endoglin deficient endothelial cells promote recruitment of monocytes/macrophages and differentiation of them can play a critical role in development of arteriovenous malformations. Will targeting macrophage recruitment or activation instead of angiogenesis result in greater understanding leading to new therapeutic targets to control disease?

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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Goal 1: Promote Human Health

How do Circulating Precursor Endothelial Cells contribute to newly formed vessels

Endothelial cells derive from cells in the bone marrow. Circulating precursor endothelial cells contribute to newly forming vessels.

Do Alk 1 and/or Endogln mutations affect the functions of these cells once they incorporate into growing vessels. These vessels then go on to form arteriovenous malformations

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, Chris Hughes PhD

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Goal 2: Reduce Human Disease

Why does loss of endoglin in adult blood cells lead to cardiac hypertrophy in HHT patients

Liver arteriovenous venous malformations creates a high flow shunt that over time creates high output cardiac failure with no effective treatments.

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, Chris Hughes PhD

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Goal 2: Reduce Human Disease

What is the role of diet and nutrition in treatment, management and prevention of Heart Failure?

Heart Failure (HF) remains a major public health burden. A working group was convened by NHLBI and ODS in June, 2013 to address the role of diet and nutrition in management of HF. A review of existing evidence produced no clear rationale for appropriate dietary interventions. On the contrary, the group developed recommendations for conducting additional research specifically on the role of sodium, fluid, nutrients, and ...more »

Submitted by (@lvanhorn)

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 summarized following the Working Group meeting,compared with the situation for cardiovascular risk factor management, there is little well-founded evidence regarding the efficacy, safety, and clinical impact of dietary modifications for patients with various HF phenotypes. The importance of diet and nutrition to promote health and prevent or control disease is well established. Research on obesity, hypertension and cardiovascular disease have contributed to the development of nutritional guidelines to prevent these disease in the general population but efforts to determine nutritional needs for the patient with HF lack high caliber evidence regarding safety, efficacy, and clinical impact of dietary modifications. The stronger evidence and focus on disease prevention and health promotion with diet modifications like DASH cannot be easily applied or extrapolated for disease management, especially HF, because of critical knowledge gaps and potential harm. Research on HF has more recently identified and differentiated medical treatment and interventions appropriate for HF with or without preserved ejection fractions. This only adds to the questions surrounding diet and nutritional approaches to help reduce and prevent HF readmissions.

Feasibility and challenges of addressing this CQ or CC :

Chronic HF often presents as a multisystem disease with important co-morbidities such as anemia, insulin resistance or diabetes, autonomic dysregulation, and impaired renal function. Intestinal dysfunction with impaired motility and circulation and disturbed intestinal barrier and flora may lead to a chronic inflammatory state and nutrient malabsorption. In advanced cases, catabolic/anabolic imbalance is associated with cardiac cachexia, a difficult to treat condition which itself carries a poor prognosis. Furthermore, psychosocial symptoms associated with HF, including depression and impaired cognition, can contribute to poor self-care and lack of adherence to recommended dietary, physical activity, and medication regimens. Nutritional status concerns for patients with HF increase with disease severity. Salt restriction is now controversial and clinicians give little attention to diet as a potential intervention to improve outcomes. Proposed recommendations:

1.Determine the correct sodium threshold; ranges of sodium and fluid intake, and the safety for sub-groups including HFPEF, HFREF, and cardiorenal syndrome. 2.Generate new knowledge which identifies therapeutic targets and understand the role of the gut microbiome on gastrointestinal malabsorption, inflammation, and protein balance in HF.

3.Apply innovative study designs to reduce evidence gaps 4.Develop technologies to facilitate nutrition research and address weight and multiple risk factors should be addressed.

Name of idea submitter and other team members who worked on this idea : Linda Van Horn, PhD, RD

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Goal 4: Develop Workforce and Resources

Bridge “translational gap”

Provide resources and training to improve the ability of scientists to bridge the “translational gap”. Continue and expand the VITA program.

Submitted by (@societyforvascularsurgery)

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 : Society for Vascular Surgery

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Goal 2: Reduce Human Disease

Can one integrate cardiac imaging studies with genetic,clinical, "omics", and historical data to predict disease and personalize

There are many novel imaging modalities, including radiographic, scintigraphic, sonographic, MR-based, and molecular for the heart and vessels. Patients have unique medical "signatures"- genetic risk factor profiles, epigenetic markings, "omics" profiles, and personal clinical and family history as well as symptom constellation and physical exam findings. Can these all be integrated into a single personalized profile ...more »

Submitted by (@dpinsky)

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

Feasibility and challenges of addressing this CQ or CC :

This will require a combination of informatics, state of the art imaging, and state of the art genetics and omics profiling with integration with the electronic health record.

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Goal 2: Reduce Human Disease

Timing of post-cardiac arrest PCI

The majority of patients who are resuscitated from OHCA have a presumed cardiac etiology. One of the key interventions post cardiac arrest is to study the coronary circulation for underlying thrombosis. Some centers do this routinely but at other centers interventional cardiologists are hesitant to do this since the mortality rates are high and so affect their individual and institutional performance measures related ...more »

Submitted by (@dayam0)

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 is variability in practice and no large scale level 1 evidence as to what is the best to do with regards to post ROSC care and PCI as well as timing of the PCI

Feasibility and challenges of addressing this CQ or CC :

Will require funding, broad cooperation between cardiologists and emergency medical services as well as critical care. National groups that conduct performance measures for survival following PCI need to readdress the use of such measures in this group of patients (post-arrest)

Name of idea submitter and other team members who worked on this idea : Mohamud Daya

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Goal 3: Advance Translational Research

Genetics and Genomics of Heart Disease

Identification of new genetic/genomic variants and risk genes often opens a new window to explore the fundamental molecular mechanisms underlying a disease and to develop new methods and strategies for diagnosis and treatment. Existing genomic variants and/or mutations explain only 10% to 20% heritability of common heart diseases. Much remains to be done in this important area. However, most genetic projects are discovery-driven ...more »

Submitted by (@wangq2)

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

Details on the impact of addressing this CQ or CC :

Identification of new genetic/genomic variants and risk genes often opens a new window to explore the fundamental molecular mechanisms underlying a disease and to develop new methods and strategies for diagnosis and treatment. Existing genomic variants and/or mutations explain only 10% to 20% heritability of common heart diseases. Much remains to be done in this important area. However, most genetic projects are discovery-driven and not hypothesis-driven, so that finding in this area has been extremely low. We recommend that genetics and genomics should be placed as a strong priority for NIH funding for the coming years.

Feasibility and challenges of addressing this CQ or CC :

Feasible

Name of idea submitter and other team members who worked on this idea : Qing Kenneth Wang

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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 1: Promote Human Health

THE RELEVANCE OF PREVENTION TRIALS

Prevention trials, implemented to reduce or delay progression to overt disease in a population at risk to the disease, are an important approach to health promotion. Therapies shown to reduce disease severity in patients with a specific disease are obvious, but not the only, candidates for a prevention trial in populations at high risk for prevalent diseases (such as heart failure, diabetes, COPD, asthma in children). ...more »

Submitted by (@media0)

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 impact of implementing such trials is considerable. They will clearly address an important component of NHLBI’s mission with respect to effectiveness of therapies and behavioral interventions, and it has minimal and clearly definable overlap with commercial trials of specific therapeutic products. It will also provide an important public health focus – preventing disease or reducing the impact of disease processes, thus potentially reducing chronic care costs and increasing years of useful life.

Feasibility and challenges of addressing this CQ or CC :

The biggest challenge in designing and implementing prevention trials is identifying the target, “at risk” population most likely to develop the clinical disease from known biomarkers or early signs/symptoms. Increasing availability of large, population-based registries or databases maintained for other purposes provides a very cost-efficient mechanism to electronically screen and identify “at risk” individuals. The same mechanism may also facilitate implementation of pragmatic, electronically managed, cost efficient trials.

Name of idea submitter and other team members who worked on this idea : Sonja McKinlay other Team Members: Susan Assmann and Paul Stark

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