Goal 2: Reduce Human Disease

Stem Cell Immunology

We now can create critical cell types like cardiomyocytes etc. from stem cells. Additionally, we are learning the rules of using these cells to rebuild tissues. A major gap in our knowledge relates to the immunobiology of these cells. Lessons from transplantation medicine are only partially applicable, because solid organs are more complex and likely more immunogenic than defined cell populations. How does the immune ...more »

Submitted by (@murry0)

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

Details on the impact of addressing this CQ or CC :

We now can generate large quantities of critical cell types whose deficiencies underlie many chronic diseases like heart failure. This breakthrough brings us to the next-level impediment: the immune system. While induced pluripotent stem cells have the potential to obviate rejection, in practical terms this is cost-prohibitive: It will cost huge amounts of money to produce and qualify a single patient's cell dose. Moreover, human cardiomyocytes are potent when given to infarcted hearts in the acute or sub-acute phase of infarction, but they have no benefit with chronic heart failure. The 6 months required to produce iPSC-cardiomyocytes precludes their autologous use for myocardial infarction.

 

We need an off the shelf cell therapy product for myocardial infarction that can be mass produced and qualified for large numbers of patients. This means an allogeneic product is necessary. Identifying the immune response to cardiomyocytes or other cell products will teach us how to precisely immunosuppress the patient, thereby minimizing complications, or alternatively, how to engineer the cells so as to avoid immunogenicity in the first place.

 

Lessons from the study of cardiomyocyte transplantation could extend to dopamine neurons, pancreatic beta-cells, retinal cells, myelinating cells and many other areas that cause common chronic disease.

Feasibility and challenges of addressing this CQ or CC :

We know a great deal of transplant immunology from hematopoietic stem cell transplantation (graft versus host) and from solid organ transplantation (host versus graft). There are good mouse and large animal (including non-human primate) models of stem cell differentiation and organ transplantation. This offers low hanging fruit where, in perhaps 5 years, we could discern the critical similarities and differences between transplanting stem cell derivatives and organ or marrow transplantation. These studies will inform clinical trials of allogeneic human stem cell derivatives that will be underway by then.

 

Success in this area will require bringing together researchers interested in stem cell biology and transplant immunology. A properly resourced RFA from NIH could be just the thing needed to promote this interaction.

Name of idea submitter and other team members who worked on this idea : Charles Murry, MD, PhD

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Goal 3: Advance Translational Research

How can we develop more selective immunosuppression for allogeneic hematopoietic cell transplantation?

Graft versus host disease (GVHD) remains the most significant complication of allogeneic hematopoietic stem cell transplantation (HCT). While the use of HCT has grown significantly safer and has demonstrated broad efficacy in the setting of a broad range of blood diseases, immunosuppressive therapy has not dramatically evolved since the introduction of calcineurin inhibitor-based approaches decades ago. The availability ...more »

Submitted by (@kkomanduri)

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

Details on the impact of addressing this CQ or CC :

GVHD remains a critical problem and major barrier to the more widespread utilization of HCT, especially for nonmalignant diseases, where tolerance of treatment-related mortality is understandably low.

 

There is a compelling need for novel immunosuppressive agents that can effectively limit alloreactivity mediated by donor T and B cells, while relatively sparing pathogen-specific T cells, including those mediating antiviral T cell responses important in the post-HCT interval.

 

In the past decade, drug development has facilitated the introduction into preclinical and clinical trials of a broad range of agents that in addition to targeting pathways of interest in target cells (e.g., aberrant signaling in cancer cells) may also effectively inhibit T and/or B cell responses. Examples include hypomethylating agents (e.g., azacitidine), HDAC inhibitors (e.g., vorinostat), MEK inhibitors (e.g., trametinib) and BTK inhibitors (e.g., ibrutinib). Each of these classes of agents has been demonstrated in preclinical and/or clinical studies to also limit alloreactive T cells, and/or augment regulatory T cell responses, leading to a net reduction of alloreactivity. Unlike traditional agents (e.g., the calcineurin inhibitors) these agents appear to be more selective, and in some cases may have dual benefit in reducing relapse.

 

The NHLBI can facilitate the identification and translation to clinical practice in the setting of HCT trials of novel immunosuppressive agents.

Feasibility and challenges of addressing this CQ or CC :

Research funding targeted to improving the pipeline of novel immunosuppressive agents could have immediate and dramatic impact in the field of HCT, especially impacting its application for nonmalignant diseases. Patients lacking optimal registry donors, especially those from underrepresented minority groups, will particularly benefit from improvements in immunosuppression, as patients receiving less than optimally matched donors are at much higher risk of GVHD.

 

The NHLBI can encourage and facilitate research that tests compounds that have already passed through the drug development process, but in many cases were not intended to function as immunosuppressive agents. Compelling preclinical studies have suggested that targeted inhibition of T and B cells, and/or epigenetic modifiers can lessen alloreactivity while preserving beneficial cellular immune responses and facilitating immune reconstitution.

 

It will be far easier to appropriate therapeutic agents already developed for another purpose than to do novel drug development from scratch. In many cases, preclinical studies have highlighted the therapeutic potential in immunosuppression for agents that have been developed to treat malignancies, but yielded suboptimal success. Research that encourages the development of these drugs as part of a combined immunosuppressive/immunomodulation approach may rescue such compounds, while yielding potential dramatic advances in clinical HCT.

Name of idea submitter and other team members who worked on this idea : Krishna Komanduri, M.D.

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Goal 2: Reduce Human Disease

Critical Challenge

• One of the most important public health issues the Nation faces is the rising incidence of heart failure. HF incidence rates have risen faster than predicted. The prevalence will increase as better and more therapy becomes available. While heart failure is the biggest ticket item in the Medicare budget, the cost to society will increase more than it has already. But much HF can be prevented or onset prolonged. Investing ...more »

Submitted by (@tsansone)

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

Details on the impact of addressing this CQ or CC :

See attached file

Feasibility and challenges of addressing this CQ or CC :

Critical Challenge

Name of idea submitter and other team members who worked on this idea : ASH Officers, Committee Members

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4 up votes
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Goal 2: Reduce Human Disease

Understanding Right Ventricular Function and Failure

There is a need for understanding of right heart failure (RHF) and its consequences following left ventricular assist device (LVAD) support, as well as to develop devices to optimally support the right ventricle.

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 :

Understanding the pathophysiology and risk factors of right heart failure in the context of LVAD use might lead to preventative and therapeutic options for these patients.

Feasibility and challenges of addressing this CQ or CC :

Current resources in terms of a National Registry for VADS (INTERMACS) exists and can be leveraged.

While we have a substantial understanding of the risk factors associated with poor outcomes of patients with heart failure and left ventricular dysfunction, much less is known about the syndrome of heart failure and right ventricular (RV) dysfunction. Right-sided heart failure occurs in approximately 20% of patients receiving LVAD support. Investigation into the pathophysiology of right ventricular failure and its consequences following LVAD support, including identification of risk factors and treatment strategies, remains a high priority according to the Joint NHLBI-American Association for Thoracic Surgery (AATS) Working Group convened in 2011 (http://aats.org/CME/2011-AATS-NHLBI-Symposium.cgi). Development of new devices designed to optimally support the RV are warranted.

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

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19 net votes
31 up votes
12 down votes
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Goal 2: Reduce Human Disease

What is the Relationship Between CVD and Dementia in the Elderly?

The successes of preventing and treating CHD, CVD has resulted in a substantial increase in life expectancy, a very important success story, but unfortunately it has led to a growing population of elderly 80+ years of age.

Submitted by (@kullerl)

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

Details on the impact of addressing this CQ or CC :

Their high prevalence of congestive heart failure (CHF), atrial fibrillation (Afib), stroke, peripheral vascular disease, dementia, frailty, and disability is clearly going to lead to the public health tsunami of the 21st century and bankrupt the health systems. Further studies are badly needed to determine the interrelationship between CVD, dementia, disability, and whether prevention of CVD beginning early in life, middle ages, or even at older ages can impact on successful aging with reduced risks of dementia and disability.

Feasibility and challenges of addressing this CQ or CC :

Older individuals with 0 coronary artery calcium (CAC) have extremely low risk of subsequent clinical CHD, CVD, and total mortality even at older ages. Whether these individuals with low risk, e.g. very low CAC, have less extensive brain abnormalities associated with increased risk of dementia needs to be evaluated.

 

The NHLBI should establish a registry of individuals who have had very low CAC scores at older ages, determine the relationship between these very low CAC scores and risk factors, genetics, and then consider trials to prevent CVD, CHD among older individuals 80+ with relatively low levels of CAC, with dementia, stroke, CHF, Afib, as primary endpoints. The NHLBI should also consider trials in middle-aged individuals to prevent the development and progression of coronary atherosclerosis, e.g. maintenance of 0 CAC. The NHLBI, in collaboration with other institutes at NIH, should evaluate the interrelationship between coronary artery atherosclerosis, e.g. CAC, and other measures of atherosclerosis, other manifestations of CVD, such as CHF, Afib, and brain changes and the development of dementia and Alzheimer’s disease.

Name of idea submitter and other team members who worked on this idea : Lewis H. Kuller, MD, DrPH

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21 up votes
18 down votes
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Goal 1: Promote Human Health

Understanding NANCs and Neuropeptide Function in the Heart

Understanding the complexity of NANC transmitter release and neuropeptide function could be helpful in establishing new, effective therapeutic strategies for treating heart disease.

Submitted by (@nhlbiforumadministrator1)

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

Details on the impact of addressing this CQ or CC :

Could lead to the development of fundamental knowledge required to develop effective new therapeutic interventions to treat heart disease.

Feasibility and challenges of addressing this CQ or CC :

Several studies have already demonstrated associations been NANC transmitter release and neuropeptide co-localization with pathogenic changes in cardiac function.

Identification within cardiac nerves of neural peptides that are co-released with traditional transmitters is an interesting and still emerging story. Studies with nonadrenergic, noncholinergic (NANC) transmitters in both the atria and ventricle have shown that a variety of neuropeptides also are localized within the heart, and several, including vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), substance P, and calcitonin gene-related peptide, have been shown to markedly affect heart rate and modulate cardiac function. NPY is also elevated in heart failure patients, and other neuropeptides, including VIP, calcitonin gene related peptide (CGRP), substance P (SP) and their receptors are associated with various types of cardiomyopathies.

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

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3 net votes
14 up votes
11 down votes
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Goal 2: Reduce Human Disease

Neurocardiology – A Challenge for Prevention of CV Disease

There is a need to recognize and study the interdependencies between the brain/peripheral nervous system and the heart/vascular systems in health and disease to develop interventions to detect, treat, and prevent cardiovascular disease.

Submitted by (@nhlbiforumadministrator1)

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

Details on the impact of addressing this CQ or CC :

Effective new therapies for treatment and prevention of cardiovascular disease

Feasibility and challenges of addressing this CQ or CC :

long recognition of interactions between neural and CV system provide a wealth of background knowledge, while new imaging and electronic designs provide means for administering novel interventions.

Presently it is recognized that the autonomic nervous system plays a major role in the pathophysiology of arrhythmias leading to sudden cardiac death (SCD), and NHLBI supports ongoing studies to determine if modulation of nerves may provide an effective means to reduce the occurrence of ventricular arrhythmias associated with SCD. Already, investigators have suggested that therapies such as right, left, or bilateral cerviocothoracic sympathectomy may provide a novel and cost effective intervention for the prevention of SCD. It is also well known that the sympathetic nervous system is activated during the onset and progression of heart failure. Currently investigators have proposed studies of specific central brain sites and the nerve supply to the heart during chronic heart failure progression to gain a better understanding of this pathway as a therapeutic target for the treatment of HF. This and the translation of results from similar studies is a challenge that should be encouraged.

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

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23 net votes
35 up votes
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Goal 2: Reduce Human Disease

Modulation of cardiac contraction and relaxation in heart failure: role of systemic inflammation

Is cardiac contraction and relaxation in heart failure modulated by the systemic inflammatory response? There is overwhelming evidence that inflammatory biomarkers predict worse outcome in acute and chronic heart failure. Despite the wealth of evidence, clinical trials in this area have either not been completed, failed, or provided inconclusive results. The questions that remain are: 1) Is inflammation a mechanism ...more »

Submitted by (@aabbate)

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 question may fill a decades-old gap in our understanding of the role of inflammation in heart failure, and potentially lead to novel prognostic biomarkers and/or improved therapeutics.

Feasibility and challenges of addressing this CQ or CC :

All the preclinical and clinical tools are available.

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

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

Predict the needs for inter and intra-hospital transfer for acute care surgery patients with respiratory failure

Density mapping of the need and flow of patients requiring acute care surgery vis-a-vis inter-facility transfer, care hand-off failures, post-acute care resource mismatch to articulate a funding plan resource allocation and development akin to what has been done for trauma care.

Submitted by (@greg.martin)

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 of Critical Care Medicine Executive Committee/Council

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2 up votes
2 down votes
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Goal 2: Reduce Human Disease

Effect of obesity on recovery of lung function in pediatric survivors of critical illness

What are the determinants of persistent respiratory failure in children? Are obese children at greater risk for prolonged mechanical ventilation than non-obese children? Does BMI affect the time to recovery of lung function in obese children with ARDS? What is the pathogenesis and molecular contributors of obesity on respiratory failure in critical illness?

Submitted by (@greg.martin)

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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3 up votes
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Goal 2: Reduce Human Disease

What do we know about Heart Failure with Preserved Ejection Fraction (HFpEF)

Mortality is similar between HFpEF and HFrEF but we have currently no viable therapeutic option for HFpEF. There have been many large trials, but they all failed. Our basic understanding of the disease is very limited which contributed to failures of many prior trials and wasting $$$. We know very little about the pathophysiology of the disease . It is time to get back to the basic science and use our new tools (e.g. ...more »

Submitted by (@rezanezafat)

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

Details on the impact of addressing this CQ or CC :

Better therapy for HFpEF is an unmet clinical needs which will impact millions of patients

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17 up votes
11 down votes
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