Goal 2: Reduce Human Disease

How gene mutations contribute to defects in vascular development

How do gene mutations in endoglin and alk 1 create arteriovenous malformations leading to disease. Alk 1 and endoglin are receptors in TGFB/BMP family signaling. TGFB/BMP have roles in vascular development, remodeling and maintenance in vascular integrity. Understanding the downstream effect will lead to advancements in reducing genetic diseases such as HHT as well as vascular malformations in general

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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3 net votes
3 up votes
0 down votes
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Goal 1: Promote Human Health

Promoting the Development of Animal and Cellular Model Systems

NHLBI might consider creating incentives for the development of core labs and national facilities to promote development of animal and cellular model systems that mimic lung injury, repair, and regeneration.

Submitted by (@skrenrich)

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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-1 net votes
3 up votes
4 down votes
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Goal 3: Advance Translational Research

Detection of inflammatory monocytes as a biomarker of CVD

Coronary artery disease (CAD), of which atherosclerosis is a major contributor, costs the United States $108.9 billion each year. While a number of conventional risk factors such as smoking, diabetes and hypertension have been associated with CAD, their predictive performance is poor in the prevention of acute coronary syndrome (ACS). Despite the prevalence of ACS in our society, there are currently no molecular biomarkers ...more »

Submitted by (@scottsimon)

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

Details on the impact of addressing this CQ or CC :

Need more opportunities to put forth innovative diagnostic and therapeutic solutions than currently vetted through the CTSC process.

We have developed the Artery-on-a-chip (A-chip), currently in a research tool format, which accurately measures the extent of inflammatory monocyte activation in a whole blood sample by shearing it along a molecular sensor and enumerating monocyte capture.

Name of idea submitter and other team members who worked on this idea : Scott I Simon, Greg Foster, Ehrin Armstrong

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-6 net votes
8 up votes
14 down votes
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Goal 2: Reduce Human Disease

Immunologic Treatment of Hematologic Malignancies

How can the use of CAR T-cell and checkpoint blockade strategies be optimized in order to cure 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 :

As the body of evidence continues to grow on the potential applications for advanced immunotherapies, next-generation research must focus on addressing the possible curative effects that checkpoint blockades or adoptive CAR T-cell strategies can have for blood diseases including hematologic cancers. This will require specific research programs to fully understand the optimal role for these therapies within the continuum of care. To optimize these strategies for treatment of hematologic diseases, studies are needed to decipher specific hematologic diseases and circumstances under which these checkpoint blockers and CAR T-cell therapies may be employed as frontline approaches. Furthermore, while the optimal approach for these therapies is unclear, advanced studies are needed to elucidate the potential benefit in combining these promising approaches and whether patients can be better identified a priori for these therapies.

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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13 net votes
28 up votes
15 down votes
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Goal 1: Promote Human Health

Environmental Exposures and Atopic Disease

As the current chair of the Research and Training Division, I would like to convey that the AAAAI membership would like the NHLBI to consider the following in the development of its strategic plan:

 

What are the molecular and cellular responses in the lung that occur after environmental stimuli (including allergens) that predict homeostatic resilience or transition to atopic diseases?

Submitted by (@wheeze)

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 : Mitchell Grayson on behalf of the American Academy of Allergy, Asthma, and Immunology

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-7 net votes
8 up votes
15 down votes
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Goal 2: Reduce Human Disease

Cellular therapy of Blood Diseases

Can modification of either autologous or allogeneic immune cells allow effective treatment of blood diseases and infection with acceptable rates of toxicity?

Submitted by (@marymh)

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

Details on the impact of addressing this CQ or CC :

Although targeted therapy is generally applied to the use of small molecules that target specific genes or proteins of diseased cells, it is now possible to target immune cells against specific diseases through genetic modification. This provides desired antigen-specificity to powerful cell-mediated cytotoxicity effects. Small studies show impressive results both in blood cancers and viral infections refractory to other therapies. Toxicity and efficacy vary with the diseases being treated and the cell products used. In addition, new approaches to genetically-modify blood stem cells are being evaluated to prevent viral infection, i.e. HIV, or correct hematopoietic stem cell derivatives, and these approaches could cure diseases for which good treatments are not currently available.

Feasibility and challenges of addressing this CQ or CC :

Both preclinical and clinical studies are needed to identify optimal cell types and gene constructs, use of “universal” donors, and magnitude and durability of clinical effects. Effective infrastructure to provide the right cells at the right time is necessary to test clinical efficacy.

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

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98 net votes
122 up votes
24 down votes
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Goal 3: Advance Translational Research

Advancing the preservation of cellular therapies

Cell therapies are produced in specialized facilities and the viability/function of the cells must be retained in order to permit transportation to the site of use, coordination with patient care, etc. Current options for preserving cells are limited. Conventional methods of cryopreservation may result in poor post thaw function and are difficult to use at the point of care. Liquid storage of cells is typically limited ...more »

Submitted by (@hubel001)

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

Details on the impact of addressing this CQ or CC :

Recent analyses suggest that the pool of patients who could benefit from stem cell-based therapies could be as high as 100 million. The actual number of patients receiving stem cell therapies is actually substantially lower than that (< 500,000). it has been postulated that one reason for the gap between the potential patient pool and the actual patient pool has resulted from poor methods of preservation. The failure of recent clinical trials using mesenchymal stem cells support that hypothesis.

Feasibility and challenges of addressing this CQ or CC :

When developing a cellular therapy, supply chain issues (e.g. preservation) is frequently ignored until the failure of a clinical trial. If preservation issues are addressed concurrently with the development of a cellular therapy, the feasibility of addressing the issue is high.

 

There are two critical challenges to addressing this critical challenge: (1) preservation studies are not considered 'sexy' and therefore score poorly in conventional study sections; and (2) organizations developing a cellular therapy do not have a team member with expertise in preservation.

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

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-12 net votes
11 up votes
23 down votes
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Goal 2: Reduce Human Disease

Making It Real: Affordable Physiologically Relevant In Vitro Environments

We have done the best we can to mimic the human internal environment in vitro for the discovery, testing, and validation of therapeutics, but there is a critical need to do better. The use of more complex cell-based in vitro models is the result of the recognition of how little predictive power there is in current experimental conditions, even with animal models. With an in vitro environment that goes beyond temperature ...more »

Submitted by (@ahenn0)

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

Details on the impact of addressing this CQ or CC :

Physiologically relevant in vitro environments could potentially impact research on every tissue type, disease, and intervention, including transfusion-based treatments. Basic research, drug-testing, and translational medicine would all be fundamentally altered. Individualized medicine, cellular therapies, and regenerative medicine could all benefit from in vitro conditions that best support the care of the patient's cells and guide those cells in the direction needed for effective treatment.

Feasibility and challenges of addressing this CQ or CC :

Research and Industry are in the early stages of developing the techniques and know-how needed to address the technical challenges in establishing human-relevant in vitro environments. We already have the technology to control in vitro oxygen and other critical gas components. Mimicking cell-cell interactions and variable cell states such as states of differentiation or stress are areas under active research. Computational and analytical techniques are being developed that can gain insight from large data sets. More of a challenge may be assessing distant effects like metabolism of drugs by the liver or potential drug and cellular interactions with the external environment. However, making a human-predictive in vitro environment affordable is the challenge that could define success or failure of any particular approach. It is feasible within the next ten years to have truly predictive in vitro environments for drug cellular therapy development.

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-4 net votes
10 up votes
14 down votes
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Goal 2: Reduce Human Disease

Heart transplant surveillance

It is essential to develop clinically viable, non-invasive, less expensive technologies for the surveillance of allograft rejection in heart transplant patients. Critical challenges that exist in the near term or long term surveillance after transplant is the unavailability of molecular and cellular level markers that can be non-invasively imaged and quantified detect rejection and thus improve patient survival. Development ...more »

Submitted by (@nhlbiforumadministrator)

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

Details on the impact of addressing this CQ or CC :

Development of methods for near term or long term surveillance after transplant can help detect the rejection and thus improve patient survival

Feasibility and challenges of addressing this CQ or CC :

The fast growth in the imaging technologies and molecular and cellular imaging technologies are gaining foot in cardiovascular sciences and should be feasible within a decade

The current surveillance to detect transplant rejection requires repeated testing with endo myocardial biopsy and catheter angiography. Both technologies are highly invasive and very expensive. Post-transplant surveillance is focused on the cellular rejection in the near term after transplant and cardiac allograft vasculopathy in the long term.

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

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1 net vote
14 up votes
13 down votes
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Goal 2: Reduce Human Disease

Triggers of cellular and molecular pathway decompensation during pulmonary exacerbations.

What triggers decompensation of cellular and molecular pathways during exacerbations of chronic lung diseases?

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 :

Elucidation of molecular and cellular pathways driving and sustaining exacerbations in chronic lung diseases. Specifically, (1) discover what perturbs antecedent conditions precipitating mal(adaptive) compensatory mechanisms leading to pulmonary exacerbation including impact of heterogeneous resilience and concomitant chronic diseases and (2) clarify response heterogeneity of longitudinal molecular and cellular signature during treatment and recovery.

Feasibility and challenges of addressing this CQ or CC :

Longitudinal pulmonary exacerbation research nested with clinical care can be initiated within 1-2 years. As part of clinical care leveraging digital education/data (electronic health/medical records and attendant meaningful use requirements), an N-of-one research design could become self-sustaining within health care systems.

Pulmonary exacerbations exhibit multiple pathogenic pathways various concurrent pathophysiological pathways, and diverse clinical manifestations. Prevention and treatment of pulmonary exacerbations is hampered by this complex biology that is dynamic and appears to vary during the course of exacerbations. Progress toward precision medicine for exacerbations may require organization of a new taxonomy for disease, which reflects a set of clinically meaningful and exploitable similarities and differences between disease traits (exacerbation polypathomics).

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

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13 net votes
23 up votes
10 down votes
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Goal 1: Promote Human Health

Environmental stimuli and the lung: predictors of homeostatic or pathological responses

What are the molecular and cellular responses in the lung that occur after environmental stimuli that predict homeostatic resilience or transition to disease, disorder, or aging?

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 :

Addressing this line of research could define biomarkers and pathways useful for prediction of how human response to an external stimulus of varied nature (i.e. microorganism, chemical, physical) could lead to specific outcomes in relationship to the duration of the exposure and the genetic makeup of the individual exposed. Identification of early signals and the pathways involved could lead to novel preventative or therapeutic approaches.

Feasibility and challenges of addressing this CQ or CC :

Methods for systems biology approaches to address complex pathobiological iterations are ready to be exploited to answer these questions.

Great progress has been made in the clarification of basic mechanisms of molecular and cellular response to environmental stimuli, in cross-sectional analyses. The continuum of the response in relationship to the genetic background of individuals responding with a homeostatic or pathological long-term outcome is missing from these data.

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

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10 net votes
15 up votes
5 down votes
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