Goal 2: Reduce Human Disease

How can we non-invasively, but still accurately, measure blood pressure in the pulmonary arteries?

Pulmonary hypertension (PH) is a complex, progressive condition characterized by high blood pressure in the lungs. The gold standard for measuring pressures in the pulmonary arteries is a right heart catheterization, where a special catheter is guided through the right side of the heart and into the pulmonary artery, the main vessel carrying blood to the lungs. This measurement is essential, as it allows physicians and ...more »

Submitted by (@katherinek)

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

Details on the impact of addressing this CQ or CC :

i. In patients with pulmonary hypertension, the use of multiple tests to characterize the type and severity has long been recommended by global experts; one commonly used diagnostic algorithm recommends more than ten different tests to accurately define this complex, heterogeneous disease. Despite the algorithm used, to confirm a diagnosis of one specific type of PH, pulmonary arterial hypertension (PAH), one must always directly measure the pressures in the heart and pulmonary artery through a right heart catheterization (RHC). Complications for this procedure are rare, but not non-existent with potentially 1 in every 100 patients having a right heart catheterization experiencing a serious adverse event (Hoeper MM 2006). Patients would significantly benefit from a non-invasive method of quantifying their pulmonary artery pressures and/or disease progression, but to date this has not been possible with echocardiography due to measurement errors (Laver 2014), CT scan due in part to measurement inconsistencies (Alhamad 2011), and cardiac MRI due to lack of standardization and multicenter trials (Peacock 2013). Not only would wider utilization of a non-invasive method of measuring pulmonary artery pressures and disease progression potentially reduce the risk from RHC, depending on the modality it could lead to earlier diagnosis of this progressive disease and/or application in countries where RHC is less common.

Feasibility and challenges of addressing this CQ or CC :

Addressing a non-invasive method of measuring pulmonary artery pressures requires investment in both technology and multicenter clinical trials to validate these measures.

Name of idea submitter and other team members who worked on this idea : Katherine Kroner, Michael Patrick Gray, PHA

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Goal 1: Promote Human Health

Iron Loss after Blood Donation and Its Effect on Donors’ Health

What is the effect of donation-induced iron deficiency on blood donor health?

Submitted by (@anne.eder)

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

Details on the impact of addressing this CQ or CC :

Blood donation removes iron, and frequent blood donors commonly have low or absent iron stores. Donation frequency remains the strongest predictor of iron depletion among all donors, after controlling for body mass, race/ethnicity, and polymorphisms affecting iron metabolism. Less well documented is the effect of iron depletion on blood donor health and well-being. Iron deficiency may have a broad spectrum of physical and neurologic consequences, including impaired work capacity, altered cognitive function, pica and restless legs syndrome. The prevalence, duration, and severity of these conditions in blood donor populations are poorly elucidated. In contrast, modest iron deficits may be protective against cancer and cardiovascular disease. Some investigators have demonstrated the feasibility to connect donor information with clinical databases to study whether donation behavior and iron status have long-term consequences for donor health.

Feasibility and challenges of addressing this CQ or CC :

Studying the short-term clinical impact of donation-induced iron deficiency presents logistical and methodological challenges. Many outcomes of interest are not observable by blood center staff under routine procedures; further, such studies are subject to selection bias due to donor failure to return to donate following low hemoglobin deferral or adverse outcomes they associate with donation. However, given the size and demographic diversity of donor populations, even uncommon outcomes can be successfully studied under a multi-center approach. A prospective approach that doesn’t condition enrollment or completion of the study on return to donate, may avoid the methodological pitfalls. A wide array of clinical or neurological outcomes can feasibly be studied with sufficient blood centers and/or donor follow-up.

Name of idea submitter and other team members who worked on this idea : Dana Devine PhD and Anne Eder MD PhD for the 2015 NHLBI State of the Science in Transfusion Medicine

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Goal 2: Reduce Human Disease

Blood Pressure Recommendation

What should be the systolic blood pressure goal for pharmacological treatment, and should it vary by age or by cardiovascular disease (CVD) risk category?

Submitted by (@nhlbiforumadministrator)

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

Feasibility and challenges of addressing this CQ or CC :

Despite fifty years of clinical trial research and forty years of national guideline activity, important clinical questions remain under intense scientific debate. The importance of these questions are underline by the scientific consensus that hypertension is most important cardiovascular risk factor globally, in fact, more important than even tobacco use.

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

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Goal 1: Promote Human Health

Epigenetics and Genomics

There is a need to investigate hemoglobin biosynthesis in order to develop novel approaches to treat sickle cell disease, thalassemia, and other anemias.

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

Details on the impact of addressing this CQ or CC :

Studies on epigenetic mechanisms have extraordinary promise for the development of transformative therapeutic approaches for non-malignant hematologic disorders, however, limited progress has been made in advancing therapies to counteract the often crippling complications of these conditions. In the case of sickle cell disease, an ensemble of proteins has been implicated in mediating the epigenetic repression of gamma-globin expression, raising the possibility that antagonizing the actions of these proteins to increase gamma-globin expression may be a useful treatment strategy. However, in certain cases, some of these proteins are deemed “undruggable,” based on their structural attributes. There is a critical need to identify druggable components of the multi-step epigenetic mechanisms as well as develop better models and assays that will more effectively identify modulators of “undruggable” proteins. Given the rich proteome and improved technologies available today, studies of proteomics, metabolomics, and regulatory RNAs are likely to reveal promising translational avenues. In addition, approaches to modifying the expression of the components of this pathway are underway using developing gene therapy strategies, such as viral vectors and/or gene editing can quickly advance therapy in sickle cell disease and β-thalassmia.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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Goal 1: Promote Human Health

Preventing hypotensive reactions and injury after blood donation

How can blood centers prevent hypotensive reactions after blood donation?

Submitted by (@anne.eder)

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

Details on the impact of addressing this CQ or CC :

Blood donation is generally safe and well tolerated by most individuals, but some people will experience syncopal reactions after donating blood, such as dizziness, lightheadedness, or loss of consciousness. Injuries which occur as a result of loss of consciousness after blood donation can rarely cause significant morbidity or disability. Although uncommon, such donation-related injuries are likely underreported because they often occur after the donor leaves the blood center. Published studies on interventions that reduce the risk of reactions have not shown an effect on preventing injuries, although some incidents might still be preventable. Physiologists have successfully treated syncope in patients with dysautonomia, in trained athletes, in astronauts, in pilots and others, using physical maneuvers with muscle tensing, to almost instantly increase venous return, cardiac output and cerebral perfusion. But studies on the use of physical maneuvers during blood donation have yielded conflicting results. Further efforts are needed to design, implement and monitor strategies to reduce injuries after blood donation and optimize donor health.

Feasibility and challenges of addressing this CQ or CC :

Injuries are most commonly associated with syncopal reactions which occur after the blood donor leaves the collection site and resumes normal daily activities. Reducing injuries will require identifying susceptible donors, providing them with postdonation instructions, and improving their ability to recognize prodromal symptoms and respond to orthostatic changes in blood pressure. Technology for personalized medicine platforms, such as mobile phone apps, could be developed to capture information about post-donation reactions and facilitate real-time interactions with blood donors. Such a system would also enable blood centers to design and deliver intervention and continuously monitor the effectiveness of the approach to prevent postdonation injuries.

Name of idea submitter and other team members who worked on this idea : Anne Eder MD PhD and Dana Devine PhD for the 2015 NHLBI State of the Science in Transfusion Medicine

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Goal 2: Reduce Human Disease

In pulmonary arterial hypertension (PAH), how can right ventricular function be improved in the setting of increased afterload

Pulmonary arterial hypertension (PAH) is a complex, progressive condition characterized by high blood pressure in the lungs and restriction of flow through the pulmonary arterial system. Significant improvements have been made in medical management with through approved pulmonary vasodilator therapies. However, long-term right ventricular afterload reductions have still not yet been achieved. The process by which the ...more »

Submitted by (@katherinek)

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 many components of the PAH disease state have evolved significantly in the past thirty years. When initially described by an NIH registry, in a time where pulmonary transplantation was the only treatment for PAH, the average life expectancy of PAH patients was estimated to be 2.8 years. Since then, 12 PAH-targeted therapies have been approved by the FDA; these therapies primarily act by dilating the pulmonary arteries in order to allow blood to flow easier through the pulmonary vascular system. Despite these advances and complex therapies, long-term afterload reduction is not achievable in most PAH patients. Patients continue to die from right ventricular failure, highlighting the important relationship of the pulmonary arterial system and right ventricle. Little is known about how and why the RV progresses from hypertrophy to full RV failure, the diagnostic signs indicating early RV failure, and how best to intervene to support the failing ventricle. Knowledge in this area is critical, however, as the RV is able to recover in many patients with severe PAH after lung transplantation. The relationship between the lung vasculature and cardiac function, and specifically a characterization of RV failure, was included as a research opportunity in the Strategic Plan for Lung Vascular Research in an NHLBI-ORDR Workshop Report (Erzurum S, et al. 2010).

Feasibility and challenges of addressing this CQ or CC :

The primary challenge of addressing this CQ on how right ventricular function can be improved in the setting of increased afterload is the comprehensive analysis and support that will need to be provided, spanning from basic to clinical science. To begin, strong support of biologic characterization of the right ventricle needs to be provided. The RV is distinctly different from the more comprehensively studied left ventricle (LV), and subsequently responds differently to changes in pressure, neurotransmitters, hormones, and pharmaceutical therapies to name only a few. However, when identified, these RV biologic distinctions can be further explored to develop a better understanding of RV failure and potential points of intervention.

Name of idea submitter and other team members who worked on this idea : Katherine Kroner, Michael Patrick Gray, PHA

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Goal 1: Promote Human Health

Nefarious substances in the US blood supply

Prescription and illicit drug is everpresent in the US, which can potentially result in controlled substances entering the US blood supply. Passive transfer of immune allergens is only anecdotally been reported as peanut allergens, fish allergens, and contrast material. However, US blood donors are only screened for a limited number of medications on the universal donor health questionnaire at time of collection. What, ...more »

Submitted by (@garrett.s.booth)

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

Details on the impact of addressing this CQ or CC :

Of the nearly 15 million blood products collected in the US (National Blood Collection and Utilization Survey), what percent of donations capture additional substances like medications and illicit substances. Healthcare providers may be unaware of potential adverse transfusion reactions that could arise from potent allergens within the products themselves.

If additional donor screening is required to reduce the number of medications/drugs entering the US blood supply, how best to do this? Via blood toxicology, urine toxicology, hair toxicology? Is there a need to marry the donor drug history with the recipient allergy list?

Feasibility and challenges of addressing this CQ or CC :

These questions would require blood collection centers to potentially revise how they screen blood donors. How and when to probe donations or donors will require extensive medical-legal investigation.

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

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Goal 3: Advance Translational Research

Genome Editing and Gene Therapy

There is a critical need for the establishment of strategies that will determine the efficacy, safety, and toxicity of genome editing techniques specifically in hematologic diseases.

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

Details on the impact of addressing this CQ or CC :

Inherited monogenic hematologic diseases such as hemophilia, beta-thalassemia and sickle cell disease are prime targets for future application of genome editing technology. However, studies are still needed to advance our understanding of the biology of genome editing as well as determine which other disorders are amenable to genome editing correction. Emphasis on preclinical research that focuses on determining the accuracy, safety and efficiency of this technology in order to help minimize off-target mutations and reduce toxicity, is essential for effective translation of this technology into the clinic. Once preclinical efficacy is established, support will be needed for clinical vector production, toxicity testing of the vectors/reagents used, and the performance of clinical trials. The gene correction strategies developed for inherited disorders will also be attractive for other hematologic diseases, and autoimmune disorders like lupus, rheumatoid arthritis, and type I diabetes). There is also a critical need for supporting preclinical validation studies, scale-up and GMP cell manufacturing, all of which could be shared infrastructures across multiple diseases in the NHLBI portfolio.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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Goal 3: Advance Translational Research

Stem Cell Biology

There is a need to develop “designer platelets” and “designer red cells,” as well as facilitate large-scale production of these products for therapeutic and diagnostic use.

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 reprogramming of adult stem cells has resulted in the generation of induced pluripotent stem cells (iPSCs) that can develop into any tissue of the body. These iPSCs ultimately may be used as a transplantable source of stem cells for a variety of hematologic diseases. Although this technology has enabled the generation of patient-specific or disease-specific stem cells that are also amenable to genetic manipulation, the major scientific hurdle has been the ability to create clinically meaningful functional blood products, including transplantable HSCs from differentiating iPSCs. The production of clinically functional blood products -- i.e. red blood cells derived from autologous iPSCs --could replace allogeneic products in highly immunized patients and the generation of megakaryocytes for patient-specific platelet production from iPSCs could drive significant progress in this area. Furthermore, disease-specific iPSCs could serve as targets for both drug development and drug screening in patients with rare hematologic disorders. In addition, support for scale-up and GMP processes, which are difficult to fund via the R01 mechanism will require specific grant opportunities tailored to infrastructure and process development.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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53 up votes
28 down votes
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Goal 3: Advance Translational Research

Genome Profiling

What structural changes need to be implemented in the health-care community in order to support the use of genomic information in clinical trials and drug development for hematologic diseases?

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

Details on the impact of addressing this CQ or CC :

In various blood disorders, including hematologic malignancies, there are both inherited and somatic genetic alterations that contribute to predisposition, transformation, disease progression, responsiveness to therapy, and treatment complications. The presence of such genetic alterations underscore the need for the identification of rare but traceable mutations as well as the integration of such genomic information into clinical trials. By implementing a few structural changes in the healthcare sector, a clinical trial infrastructure can be established that accounts for proper application of sequencing technology. Some examples include the creation of genome diagnostic networks that address accrual of sufficient patients, procurement of suitable tumor/non-tumor material for sequencing, as well as pharmacodynamic and correlative biology studies in hematologic diseases.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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Goal 3: Advance Translational Research

To find specific medical therapies to treat the wide array of human vascular malformations and vascular tumors.

Vascular malformations and vascular tumors, together referred to as vascular anomalies, comprise a complex and wide array of diseases in which there is a fundamental disruption in blood and lymphatic vasculature. The lesions disrupt organ function, destroy tissue, cause bleeding, increase infections and can threaten life. At present, there are some medical therapies but none are specifically targeted to an underlying ...more »

Submitted by (@joyce.bischoff)

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

Details on the impact of addressing this CQ or CC :

Deciphering the cellular and molecular basis of human vascular anomalies will have a critical impact for patients with these lesions and it will also have a broad, far-reaching impact on cardiovascular research because the mechanisms and insights learned from these specific vascular anomalies will teach us the fundamental rules that are needed, and must be followed, to build and maintain a stable functional vasculature in humans. This will have an impact on a variety of areas of research including regenerative medicine.

Feasibility and challenges of addressing this CQ or CC :

With the enormous advances in next generations sequencing technologies, the time is ripe for a concerted push to find the gene mutations that cause human vascular malformations and vascular tumors, both the most common and the rare. Cellular models for human endothelial cells are vastly improved and far superior to murine endothelial models, making research on patient-derived cells highly feasible.

The challenges will be to develop animal models of the individual human vascular anomalies that reflect as closely as possible the critical and specific features of the vascular malformation or vascular tumor. Such animal models, as well as relevant cellular in vitro models, would then be ideal for screen drug libraries for ability to reverse or slow the formation of the malformation or tumor. Such drugs might then be candidates to test in pilot clinical trials.

Name of idea submitter and other team members who worked on this idea : Joyce Bischoff

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Goal 1: Promote Human Health

Mechanism of dietary polysaccharide/ sugars in averting CVD and cancer

CQ

Submitted by (@mayaraman)

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

Details on the impact of addressing this CQ or CC :

Non-communicable diseases and their preventive measure are always of interest. But we always, face side-effects because of these new applications. And at times, these techniques fail.

Diet today is a attractive area of discussion. Everyday, we read or hear that control of diet has cured severe conditions.

In fact, as the saying goes, we are what we eat. Today, scientific communities can lay emphasis on the researches concerning these topics. Dietary polysaccharides/ polyphenols etc. have a promising role in deciding our health. We can include these in our diet but the mechanism of the action of these factors in preventing diseases has not be explored in detail. The role of specific factors in diet at specific sites, may assist in pin-point treatment with better results and no side-effects. Can this topic be considered for research!

Feasibility and challenges of addressing this CQ or CC :

Challenges include creating teams of researchers with basic research expertise and experienced researchers to collaborate and come up with plans to understand the action of system and to design strategies utilizing dietary carbohydrates to have healthier and long term benefits.

Name of idea submitter and other team members who worked on this idea : Raman M

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