Goal 2: Reduce Human Disease

Lung progenitors and disease

What is the role of lung stem/progenitor cells in disease?

Which diseases involve stem cell defects?

Submitted by (@nhlbiforumadministrator1)

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

Harnessing Lung Regenerative Capacity to Improve and Increase Donor Lungs for Transplantation.

Using knowledge of matrix biology and lung development, what are useable methods to modify cadaveric donor lungs to provide a durable, effective organ replacement therapy?

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 :

A major advance in this area will increase the number of donor lungs available for lung transplantation

Feasibility and challenges of addressing this CQ or CC :

A number of stem and progenitor cells involved in lung repair and regeneration have been identified. Targeting them for expansions in damaged donor lungs may turn these damaged lungs into healthier lungs that can then be used for lung transplant safely.

Most of the donor lungs are not suitable for lung transplantation because the premorbid conditions of the donors often also damaged the lungs. Bioreactors have been used to “rehab” these damaged lungs and optimizing the ex vivo condition in these bioreactors may accelerate the lung repair process.

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

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Goal 1: Promote Human Health

The coupling of mechanical stress to biochemistry, molecular biology and electrophysiology

Cells aren’t beakers holding soluble reactants waiting to be mixed. Cells are structured objects where life forms as a flow of free energy between three pools: chemical, electrical and mechanical. Most papers in the literature ignore structure (except of Xray or EM of specific proteins) and almost all ignore the coupling of mechanics to the other pools. Cells cannot be studied with in vitro experiments. We can study single ...more »

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 :

If we learn how a third of all cellular energy is used we have a better chance of understanding the other 2/3.

Feasibility and challenges of addressing this CQ or CC :

See more at: http://grants.nih.gov/grants/guide/notice-files/NOT-HL-15-252.html#sthash.7xHiSbcd.dpuf

Name of idea submitter and other team members who worked on this idea : Dr. Frederick Sachs

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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

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

Translational Research for HIV/AIDS and HLB Health and Diseases

What are the best inroads for the NHLBI to support innovative approaches in the next 5-10 years, especially blood cell therapies based on hematopoietic stem cell and novel gene therapy approaches to control or even cure HIV infection?

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 :

HIV control or possibly even HIV cure could result from developing novel cell therapies, especially hematopoietic stem cell (HSC) transplants, and might also result from early use of antiretroviral therapy in acutely HIV-infected individuals.

• Transplantation of HSC including engineered cells has the potential to eradicate HIV reservoirs for HIV cure: the Berlin patient treated with HSC transplant remains free of HIV and is still the only patient cured of HIV infection as of today;

• Identification of acute HIV infections through routine blood donor screening and early anti-retroviral therapy for identified HIV-infected donors can limit or even prevent the establishment of HIV reservoirs.

Feasibility and challenges of addressing this CQ or CC :

• The Berlin patient has provided the proof of concept that HIV infection can be eradicated, that is, sterilizing cure can be achieved, through HSC transplantation in combination with other therapies;

• Recent studies have shown that early identification of HIV infection and treatment of infected individuals with anti-retroviral therapy as soon as possible can significantly limit the size of the HIV reservoirs even if such early treatment may not be able to completely prevent the establishment of HIV reservoirs; routine blood donor screening for both anti-HIV antibodies and HIV RNA among blood donors offers unique opportunities to identify acute HIV infections.

 

 

For HIV cure, the challenges include:

 

• Generation of HIV-resistant HSCs in adequate quantity for transplantation;

 

• Efficiency of homing and expansion of HIV-resistant HSC transplants;

 

• Efficiency in replacing HIV-infected cells, including CD4+ resting cells as the major HIV reservoirs, with HIV-resistant HSCs following transplantation;

 

• Efficiency in immune reconstitution by HSC transplants;

 

• Safety of HSC transplantation with needed GVHD to eliminate HIV-infected resting T cells while avoiding irreversible damage to the host.

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

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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 1: Promote Human Health

Mechanisms of Vascular Stiffness

Increased vascular stiffness has been identified as an important cardiovascular event that accompanies aging and cardiovascular disease. Although multiple vascular changes have been identified and suggested to cause increased vascular stiffness, our understanding of the underlying mechanisms needs to be refined in order to develop useful therapeutic strategies to prevent or reverse these changes. An example of critical ...more »

Submitted by (@meiningerg)

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

Details on the impact of addressing this CQ or CC :

Ultimately, addressing this CQ would impact treatment of CV disease, reduce incidence of significant and life threatening CV events and improve quality of life. This area of investigation is relevant to therapeutics and potentially lifestyle changes that will improve CV health and slow CV age related changes linked to disease.

Feasibility and challenges of addressing this CQ or CC :

Current advances in our technologies make it very feasible to address new questions to improve our knowledge of the mechanisms underlying vascular stiffness. Challenges will include developing multi-scale and cross disciplinary strategies that will, by design, facilitate an integrated understanding of the process leading to altered vascular stiffness.

Name of idea submitter and other team members who worked on this idea : Gerald A. Meininger

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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)

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 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 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 2: Reduce Human Disease

Engineered ECM for heart repair

Utilizing advances in nano, bio, tissue and related engineering technologies to construct cardiac ECM for heart repair.

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 :

Will advance cell and gene based therapeutics for cardiac repair. Despite promise, efficacy of cell based therapies remains largely unproven and this may in part be due to poor understanding of cell-ECM interactions. Research efforts in engineering cardiac ECM have the potential to greatly advance such therapeutic approaches.

Feasibility and challenges of addressing this CQ or CC :

This research field is ripe for experimentation and testing.

A major thrust of recent efforts in repairing cardiac injury has focused on cell therapies. However, since the ECM provides the necessary scaffold for the cells it is important to consider the cell-ECM interactions when utilizing these approaches.

 

Will require multi-disciplinary expertise.

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

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Goal 3: Advance Translational Research

Genomics in transfusion medicine

How can RBC genomics be utilized to improve outcomes with transfusion?

Submitted by (@barbarak)

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

Details on the impact of addressing this CQ or CC :

Prevention of alloimmunization with transfusion

Improved understanding of RBC epitope diversity

Feasibility and challenges of addressing this CQ or CC :

Utilize advances in genomics medicine to better understand impact of transfusion and to improve outcomes.

Limited donor pool, particularly in minority populations, presents challenges

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