Goal 3: Advance Translational Research

Can hair follicle stem cells be transformed into new cells or organs?

Dr. Cotsarelis of the Univ. of Pennsylvania identified the bulge area of the hair follicle, which is now thought to contain the hair's stem cells. These cells would seem to be readily available and unique to an individual person. Can further work be done to transform these cells into now only hair cells but other organ tissues?

Submitted by (@info00)

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

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Goal 1: Promote Human Health

Endoglin Regulates biolgy and signal transduction in vascular smooth muscle cells

Why loss of endoglin causes HHT is not known. Endoglin is expressed by vascular smooth muscle cells and endothelial cells.

What is the role of endogin on vascular smooth muscle cells and why its loss contributes to HHT and other vascular malformations

Submitted by (@mariannes.clancy)

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

Details on the impact of addressing this CQ or CC :

Vascular smooth muscle cells wrap around arteries and control their diameter.

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

Genetic engineering in lung progenitor cells

Can genome engineering be used to correct or alter lung stem/progenitor cells to ameliorate lung disease and promote regeneration?

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 : NHLBI Staff

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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 2: Reduce Human Disease

Human Lung Progenitor Cells, Lung Epithelial Differentiated iPSCs, and Therapeutics

What are the biological properties and key surface markers of human lung progenitor cells and lung epithelial differentiated iPSCs? How can these cell populations be targeted for therapeutic purposes, including regenerative therapy?

Submitted by (@skrenrich)

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 : Cystic Fibrosis Foundation

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Goal 2: Reduce Human Disease

Mitigating risks due to the RBC storage lesion and vulnerable patients

What are the underlying dependencies (genomic, metabolic, disease) in individual donors that either accelerate or delay the changes to red blood cells during refrigerated storage? What methods of preparation might protect patients from the risks posed by the accelerated degradation of RBCs provided by "poor storers"? What characteristics of individual patients make them particularly vulnerable to transfusion of red ...more »

Submitted by (@andrew.dunham)

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 changes in red blood cells during refrigerated storage have been well documented and associated with negative clinical sequelae in the peer reviewed literature. While the impact of this so-called storage lesion does not impact every patient during every transfusion it is reasonable to expect that when a unit of blood is transfused to a particularly vulnerable patient from a donor that has red blood cells pre-disposed to degradation, stored in a manner that has allowed significant change to occur, the risk of a negative clinical sequelae is increased. In this case it will be important to understand what underlies the likelihood of a donors blood to store poorly, the changes that occur during storage that could impact vulnerable patients and design approaches to mitigate the degradation that could result.

Feasibility and challenges of addressing this CQ or CC :

We believe mitigating the impact of the storage lesion is feasible by reducing and controlling the oxygen concentration in the RBC unit prior to refrigerated storage. We are continuing our development of a device to do this and to generate the data demonstrating the effect of deoxygenation and anaerobic storage.

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

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Goal 2: Reduce Human Disease

Biology of the intact alveolar wall – the new frontier in lung research

HOW DO WE STUDY THE BIOLOGY OF THE INTACT ALVEOLAR WALL IN THE CONTEXT OF LUNG DISEASE AND REPAIR?

Submitted by (@jb3900)

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

Details on the impact of addressing this CQ or CC :

SEE UPLOADED FILE

Feasibility and challenges of addressing this CQ or CC :

SEE UPLOADED FILE

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

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Goal 2: Reduce Human Disease

The role of Extracorporeal Photopheresis (ECP) in the prevention and treatment of rejection of heart and lung transplants

According to the ISHLT, more than 4,000 patients undergo a heart transplant each year, and almost 4,000 receive single or double lung transplants. Their prognosis depends heavily on the avoidance of rejection, which claims the majority of their lives. For heart transplant recipients, the median survival is 11 years, while for lung transplant recipients, it is approximately 5 years. The current most common anti-rejection ...more »

Submitted by (@mmarques)

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

Details on the impact of addressing this CQ or CC :

Patients who are fortunate to receive a matched heart or one or two lungs transplants are at high risk of dying from rejection early and even years after the operation. Thus, they are given cocktails of highly toxic anti-rejection drugs for the rest of their lives. Unfortunately, despite compliance with their drug regimens, many patients still suffer repeated episodes of rejection that may be fatal. In addition, they develop serious side-effects such as diabetes, infections, malignancies, renal failure, etc. ECP has been shown efficacy in preventing and treating cardiac transplant rejection, but the data are limited. ECP appears to benefit such patients by causing an increase in the number of circulating T regulatory (“T regs”) cells. T regs are known to mediate immune tolerance, the ultimate goal of a long-term successful transplant. The role of ECP in lung transplantation is mostly unknown. Very preliminary data have been gathered from retrospective studies. We suspect that patients with early bronchiolitis obliterans syndrome (“BOS”) will benefit from ECP prior to developing irreversible pulmonary damage. In both types of transplants, however, it is unknown when should ECP be started, how often it should be employed (treatment schedule), and for how long. Finally, the most compelling argument to use ECP in heart and lung transplantation is its excellent side-effect profile. Furthermore, ECP may allow a decrease in the number of drugs needed to prevent rejection.

Feasibility and challenges of addressing this CQ or CC :

Many patients with heart and lung transplants develop severe and often fatal rejection despite the current drug options to prevent rejection. ECP could be added to their treatment regimens and decrease side-effects, improving long-term survival.

 

ECP is generally well tolerated and complications are extremely infrequent.

 

There is a great potential for multi-disciplinary collaboration between Apheresis Medicine, Cardiology, and Pulmonary specialists.

 

It is conceivable that manufacturers of ECP instruments will be interested in contributing to the design and support of these studies.

 

Such studies could shed light in the mechanism of action of ECP in heart and lung transplantation.

 

There is a need to develop standardized treatment regimens based on well designed clinical trials to further optimize the use of ECP. Development and standardization of measurable outcomes is critical for the success of clinical studies in apheresis in general, and ECP in particular.

 

Challenges:

1. Limited number of institutions providing ECP treatment.

2. Cost of ECP procedures.

3. Small number of animal models available for apheresis research. Thus, limited studies of ECP mechanism(s) of action. However, understanding pathological mechanisms and their relationship to response to apheresis is critical for optimization and advancement of patient care in heart and lung transplantation.

4. Lack of infra-structure for apheresis research.

Name of idea submitter and other team members who worked on this idea : Marisa Marques on behalf of ASFA

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Goal 3: Advance Translational Research

Increasing Regenerative Medical Strategies in Pulmonary Arterial Hypertension

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. Current PAH therapies mainly act of the vasoconstrictive component of the disease; however there is a widely accepted view that another contributor to the disease is an abnormal overgrowth of cells that line the pulmonary arteries, which ...more »

Submitted by (@michaelg)

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Details on the impact of addressing this CQ or CC :

In the past twenty years, 12 PAH targeted-therapies have been approved by the FDA. This increase in disease state awareness and in the treatment armamentarium have contributed to an increase in average survival from 2.8 years to an estimated 8-10 years. However, current treatments primarily address the vasoconstrictive component of the disease and do not address the now accepted theory of post-apoptotic overgrowth of hyperproliferative cells of the pulmonary vessels. A number of circulating stem and progenitor cells, derived from the bone marrow, have been identified that could have roles in repair of the pulmonary vascular system when interacting with the quickly, abnormally growing cells in the lung vessels. Work in this area has been named as a future research opportunity in the NHLBI-ORDR Strategic Plan for Lung Vascular Research (Erzurum S, et al. 2010).

Feasibility and challenges of addressing this CQ or CC :

Basic and translational research support is needed—including high-throughput approaches such as phage display and large-scale proteomic analysis—to better understand the relationship between circulating bone marrow-derived cells, lung-resident stem and progenitor cells, and endothelial cells of the pulmonary arterial system.

Name of idea submitter and other team members who worked on this idea : Pulmonary Hyeprtension Association, Michael Gray, Katie Kroner

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Goal 2: Reduce Human Disease

Influence of the Gut Microbiome on Pulmonary Immunity in HIV-Infected Individuals

It has become increasingly clear that gut microbiota have a tremendous impact on human health and disease. While it is well known that commensal gut bacteria are crucial in maintaining immune homeostasis in the intestine, there is also evidence of indirect effects on the lung. Multiple studies have shown that alterations in gut microbiota can lead to severe defects in pulmonary immune responses and reduced ability to ...more »

Submitted by (@brent.palmer)

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Details on the impact of addressing this CQ or CC :

HIV-infected individuals are at significant risk of developing and dying from infectious and non-infectious pulmonary complications. Alteration of gut microbiota have been shown to have dramatic effects on pulmonary immunity and severity of lung infections. For instance, multiple studies have indicated that probiotic treatment with certain Lactobacillus and Bifidobacterium strains results in reduced incidence and severity of upper respiratory tract infections in children. Similarly, a recent study showed that treatment with the minimally absorbed antibiotic neomycin was associated with alterations in gut microbiota composition and concomitant reduced pulmonary immunity and the inability to control Influenza infection in mice. It was recently described that HIV infection is associated with a dramatic alteration in gut microbiota and that these changes persist with antiretroviral therapy (ART). Thus, it is important to understand how these alterations may effect lung immunity, since the majority of HIV-infected individuals develop pulmonary infections. Furthermore, gut microbiota contribute to development of non-infectious complications such as atherosclerosis, metabolic disease, obesity and diabetes. It is thus highly plausible that the gut microbiota may also play a role in the development of non-infectious complications of the lung such as Chronic Obstructive Pulmonary Disease and Pulmonary Hypertension, the rates of which are elevated in HIV-infected individuals.

Feasibility and challenges of addressing this CQ or CC :

A better understanding of how alterations in gut microbiota associated with HIV infection affects pulmonary infectious and noninfectious complication could lead to therapies to protect this “at risk” group. Furthermore, manipulation of the gut microbiota in HIV-infected individuals using pro- and/or pre-biotics, antibiotics or diet modification to a composition that is associated with increased pulmonary immunity, reduced infections and lung complications are all low risk therapeutic strategies that could substantially improve lung heath in these individuals.

Name of idea submitter and other team members who worked on this idea : Brent Palmer (NHLBI-INHALD group member) and Catherine Lozupone

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Goal 3: Advance Translational Research

Regenerative Medicine 2.0 in Heart and Lung Research - Back to the Drawing Board

Stem cell therapies have been quite successful in hematologic disease but the outcomes of clinical studies using stem cells for cardiopulmonary disease have been rather modest. Explanations for this discrepancy such as the fact that our blood has a high rate of physiologic, endogenous turnover and regeneration whereas these processes occur at far lower rates in the heart and lung. Furthermore, hematopoietic stem cells ...more »

Submitted by (@jalees)

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Some barriers to successfully implementing cardiopulmonary regeneration include the complex heterogeneous nature of the heart and lung.

 

Hematopoietic stem cells can give rise to all hematopoietic cells but the heart and lung appear to contain numerous pools of distinct regenerative stem and progenitor cells, many of which only regenerate a limited cell type in the respective organ. The approach of injecting one stem cell type that worked so well for hematopoietic stem cells is unlikely to work in the heart and lung.

 

We therefore need new approaches which combine multiple regenerative cell types and pathways in order to successfully repair and regenerate heart and lung tissues. These cell types will likely also require specific matrix cues since there are numerous, heterogeneous microenvironments in the heart and lung.

 

If we rethink our current approaches to regenerating the heart and lung and we use combined approaches in which multiple cell types and microevironments are concomitantly regenerated (ideally by large scale collaborations between laboratories), we are much more likely to achieve success.

 

This will represent a departure from the often practiced "Hey, let us inject our favorite cell" approach that worked so well in hematologic disease but these novel, combined approaches targeting multiple endogenous and/or exogenous regenerative cells could fundamentally change our ability to treat heart and lung disease.

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

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Goal 2: Reduce Human Disease

Do we yet know all of the Resident Cellular Components of the Human Lung?

The DLD, NHLBI workshops conducted and published (Reference 1, 2, 3) had as their purpose to stimulate research that would identify still obscure or novel cellular components of the human lung to determine cell function in promoting respiratory tract development and in health that contributes to disease, so that better therapy might result. With robust technologies now available, especially genomic advances, how much ...more »

Submitted by (@nhlbiforumadministrator1)

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 completely understand how the human lung responds and reacts to inhaled or aspirated particles, microbes, and environmental antigens, etc.; then initiates innate and/or acquired adaptive immunity; or creates a milieu wherein cancerous cells that have travelled to the lung can establish metastatic sites, we must identify, characterize through special phenotyping and cellular function, and isolate for ex vivo study the still understudied and unknown properties of a sizable number of the 40 resident cell types in the human lung.

 

Knowledge about all the resident cells in the human lung and their functions should enhance understanding of the respiratory tract in health and disease.

 

References:

1. Needs and opportunities for research in hypersensitivity pneumonitis.

Fink JN, et. al.

Am J Respir Crit Care Med. 2005 April 1;171(7):792-8. Review.

 

2. The mysterious pulmonary brush cell: a cell in search of a function.

Reid L, et. al.

Am J Respir Crit Care Med. 2005 July 1;172(7):136-9. Review.

3. Resident cellular components of the human lung: current knowledge and goals for research on cell phenotyping and function.

Franks TJ, et. al.

Proc Am Thorac Soc. 2008 Sep 15;5(7):763-6. Doi: 10.1513/pats.200803-025HR.

Feasibility and challenges of addressing this CQ or CC :

Technologies seem available.

Name of idea submitter and other team members who worked on this idea : Herbert Y. Reynolds, M.D.

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