Goal 2: Reduce Human Disease

Targeting Inflammation in Venous Thromboembolism

What is the role of inflamation in venous thromboembolism, both DVT and PE. If the inflammatory response can be controlled, then clot formation should be able to be decreased or eliminated without bleeding potential. The effect of the inflammatory response on the wall of the veins, both in the legs and the lungs, leads to changes that result in pain and swelling (legs) and pulmonary artery hypertension (lungs). Inhibiting ...more »

Submitted by (@thomasww)

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 would suggest that studies addressing this issue using new targeted anti-inflammatory medications be supported in both large animal models (close to human) and in clinical translational studies.

Feasibility and challenges of addressing this CQ or CC :

This is feasible and doable - there is data suggesting that inflamatory inhibition with agents that target the selectins (for example) lead to a lessening of thrombosis, and decreases in vein wall damage, all without bleeding potential. These conepts in animals need to be evaluated in clinical studies. Additionally, there are other off-shoots such as studies with biomarkers of inflammation and how they can be helpful in making the diagnosis and predicting the response to therapies.

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

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Goal 2: Reduce Human Disease

Assess the true impact of sickle cell trait on cardiovascular health across then age spectrum

Sickle cell disease is now understood as a disease of inflammation in addition to abnormal red blood cells. It is likely persons with sickle cell trait are also negatively affected by the damage caused by inflammation. There is a significant racial disparity in hypertension, stroke, and chronic kidney disease. It remains unclear the degree to which sickle cell trait contributes to this disparity. It also remains unclear ...more »

Submitted by (@juliewashko)

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

Details on the impact of addressing this CQ or CC :

Recent evidence in the United States emphasizes the possible health risks for individuals with HbAS including increased incidence

of renal failure and malignancy, thromboembolic disorders, splenic infarction as a high altitude complication, and exercise-related sudden death. Additional concerns include the increase risk of hypertension from endothelial scaring and additional vascular abnormalities. Early preventative therapies for persons with HbAS (sickle cell trait) could reduce the progression of cardiovascular disease in manny individuals if found to be of concern.

Feasibility and challenges of addressing this CQ or CC :

1. Several identified impediments to research of sickle cell trait have included under-representation of the African– American community in preclinical and translational research projects and limited study in health disparities research (Am J Hematol . 2012 March ; 87(3): 340–346).

2. Ethical considerations in screening athletes and other individuals seeking labor intensive occupations for sickle cell trait

3. The diagnosis of the carrier state for a genetic disease may be associated with serious health problems that can lead to widespread bioethical and social stigmatization and additional concerns including the increased need for testing and counseling

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

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Goal 2: Reduce Human Disease

The Use of Therapeutic Apheresis to Reduce Circulating Levels of Galectin-3 and other Cancer and Inflammation Promoting Factors

Inflammation plays roles in cancer initiation, promotion, and progression. Elevated circulating galectin-3 (Gal-3) protein and other cancer and inflammation promoting factors (CIPFs) such as C-reactive protein and VEGF are associated with tumorigenesis and may play causative roles. Plasma Gal-3 is a biomarker, prognosticator, and pathogenic mediator of diverse cancers and is emerging as a therapeutic target. Preliminary ...more »

Submitted by (@elaine)

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

Details on the impact of addressing this CQ or CC :

Apheresis therapy in a clinical setting, both alone and in combination with conventional protocols, shows great potential to enhance treatment regimens, reduce dosage and side effects, improve drug deliver to target tissues, reduce long term treatment related morbidity and improve outcomes with significant benefits for patients with a broad range of cancer types and stages.

Feasibility and challenges of addressing this CQ or CC :

The need for well designed, randomized clinical trials would be readily feasible with the appropriate IND. Grant support will be needed for further development of this concept, as well as to develop columns with more optimized and specific capabilities, in addition to clinical trials demonstrating efficacy.

 

Apheresis is highly underutilized and underfunded in the US, while Apheresis research and development is much more advanced and widely utilized in Europe and Asia.

Name of idea submitter and other team members who worked on this idea : Isaac Eliaz, MD

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40 up votes
7 down votes
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Goal 3: Advance Translational Research

Develop Targeted Therapeutics to Treat Venous Thrombosis and Inflammation in Venous Thromboembolism

Venous Thromboembolism (VTE) afflicts nearly a million Americans yearly, has a mortality of 6-12% and has costs of more than $15 billion. Current treatment regimens, systemic anticoagulation and compression stockings, fail patients in multiple ways: risk of major bleeding episodes; failure of clot resolution in up to 50% of patients; failure to prevent the development of post-thrombotic syndrome (PTS) in up to 40% of ...more »

Submitted by (@chanduvem)

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

Details on the impact of addressing this CQ or CC :

Venous Thromboembolism (VTE) is a common disease with established treatment regimens that have been repeatedly proven to fail patients. The disease process affects a million Americans, and projections are that this will increase to 1.82 million by 2050. VTE affects a wide range of the U.S. population including young pregnant women, cancer patients ,hospitalized patients and the ever expanding elderly sector. Despite recent advances the incidence of the disease is unchanged and treatment failures include failure to resolve clot, failure to prevent long-term recurrence and failure to treat vein wall inflammation which results in the development of post-thrombotic syndrome (PTS) in up to 40% of patients. There are significant complications from the approved systemic treatment regimens including bleeding from anticoagulation therapy and potentially fatal complications from inferior vena cava filters. In cases of severe chronic venous insufficiency (CVI), a common sequela of VTE, quality of life survey results mirror those of chronic lung disease, coronary disease and debilitating arthritis. The cost of VTE is nearly $15.5 billion in the U.S. alone. PTS significantly affects patients and up to 42% of patients lose workdays with a cost per patient of $11,667 and a cost to the overall system of $16 billion. Addressing this critical challenge will help to decrease mortality and morbidity in a large, active sector of the U.S. population and save the healthcare system billions.

Feasibility and challenges of addressing this CQ or CC :

This critical challenge comes at an opportune time as multiple platforms for targeted therapies have been tested, proven to be efficacious and nearing approval for use in patients. Basic science research in venous thrombosis has advanced significantly with well established in-vitro and in-vivo models. Furthermore, significant work has been done to reveal multiple targets for clot resolution and for the treatment of vein wall inflammation. Thus the critical information is known and therapeutics available to make addressing this challenge highly feasible.

There will be challenges to addressing this clinical need. The first challenge may be developing and/or identifying the most relevant animal model. There are multiple established animal models and these may need to be modified to provide the best simulation of the clinical situation being addressed. Secondly, there are multiple delivery platforms that would be suitable to this project including nanomedicine based therapies. These would have to be optimized and tested in this research realm and then would need FDA approval . Lastly, following pre-clinical studies it will take large scale clinical studies to prove the efficacy and then require re-education to adopt this approach in the treatment of patients with thrombosis. Fortunately understanding and addressing these challenges will ultimately result in an improved therapy for patients with venous thromboembolism.

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

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

Impact of lung remodeling on congestive heart failure progression

End stage congestive heart failure (CHF) causes intensive lung remodeling beyond the type-2 pulmonary hypertension. CHF induced lung remodeling includes profound lung fibrosis, lung vascular remodeling and lung inflammation. Understanding CHF-induced lung remodeling is also critical to understand the right ventricular failure. However, this area is largely unstudied. Regulating CHF-induced lung remodeling and the underlying ...more »

Submitted by (@chenx106)

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

Details on the impact of addressing this CQ or CC :

To deal end-stage CHF will need team efforts from heart, lung, blood and immunology.

Name of idea submitter and other team members who worked on this idea : Yingjie Chen, Associate Professor, University of Minnesota

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Goal 2: Reduce Human Disease

Enhanced Pain Research in Sickle Cell Disease

There is a need for more enhanced pain research in order to help improve sickle cell disease patient outcomes and quality of life.

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

Details on the impact of addressing this CQ or CC :

Pain is the most common clinical manifestation of sickle cell disease (SCD) and accounts for a large proportion of emergency department visits and hospitalizations. Due to its impact on the patients’ quality of life, there is a need for more basic and clinical research studies focused on understanding the mechanisms of different pain syndromes as well as the role of neurotransmitters and inflammation in acute and chronic SCD pain. Also, comparative effectiveness studies in the management of chronic pain will be crucial in helping to improve the patients’ overall quality of life.

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 2: Reduce Human Disease

Intervening on Metabolic Derangements Induced by Allogeneic Hematopoietic Stem Cell Transplantation

Can standardized screening, pharmacological/behavioral prevention, and optimized treatment of metabolic complications after allogeneic hematopoietic stem cell transplantation improve outcomes and decrease transplant-related morbidity and mortality?

Submitted by (@madan.jagasia)

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 development of type 2 diabetes mellitus (DM) is a significant complication for long-term cancer survivors including patients treated with allogeneic hematopoietic stem cell transplantation (HCT). New onset, post-transplant DM (PTDM) occurs in up to 60% of HCT recipients, often precedes the development of acute GVHD, and negatively impacts survival. Type 2 DM is a complex disorder characterized by hyperglycemia, insulin resistance, and relative insulin insufficiency. The transition from insulin resistance to diabetes is associated with an inflammatory milieu characterized by the accumulation of IFN-γ secreting T cells (Th1 cells) and depletion of immunosuppressive Foxp3+ regulatory T cells in visceral organs and adipose tissue. Similarities exist between the immunology of insulin resistance and GVHD. However, the initiating events and mechanisms that culminate in PTDM development remain understudied, and formal recommendations for screening and treatment are lacking. All pregnant women undergo screening for diabetes, which complicates 2-10% of pregnancies in the United States. About 30% of renal transplant patients develop diabetes (NODAT), and current recommendations include weekly fasting blood glucose measurements. No such recommendations exist for HCT recipients, of whom up to 60% will develop de novo PTDM. Through clinical investigation, effective strategies for screening, preventing, and optimally treating PTDM can be developed and HCT outcomes improved.

Feasibility and challenges of addressing this CQ or CC :

It is time to make up for lost (scientific) ground. It will require the efforts of a large network like the BMT-CTN to quickly address problems, answer important scientific questions, and raise awareness for a frequent but understudied complication following HCT.

Name of idea submitter and other team members who worked on this idea : Brian Engelhardt and Madan Jagasia, Vanderbilt University

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Goal 2: Reduce Human Disease

Cellular senescence and age-related lung disease?

What is the role of cellular senescence in age-related lung disease? Do environmental factors, including smoking, contribute to the pathogenesis of lung disease through their ability to induce premature senescence? Does the accumulation of senescent cells in distal organs contribute to age-related lung disease through systemic inflammation?

Submitted by (@ferrucciogalbiati)

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 : Ferruccio Galbiati

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Goal 1: Promote Human Health

The Human Virome and Host Interactions in Heart, Lung, and Blood

What are the unknown elements of the human virome, and what host-virome interactions affect the heart, lung, and blood health and diseases? A major challenge has been the need for in vitro culture systems and animal models for studying the virome, which is a significant limitation that has forced current studies of the virome to be mostly descriptive. NHLBI has supported one research group to identify human virome and ...more »

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 :

• The virome contains the most abundant and fastest mutating genetic elements on Earth. The human virome is constituted of viruses that infect host cells, virus-derived elements in our chromosomes, and viruses that infect the broad array of other types of organisms that inhabit us. The virome may influence the host in profound ways independent of classical viral disease. The immune system is continuously stimulated by chronic systemic viruses and this aspect of host-microbiome interactions appears specific to the virome. The virome is considered one of the drivers of idiopathic systemic inflammation that has been linked to many of the most severe public health threats, including cardiovascular diseases. Disruptions in immunity by immunosuppressing events can undoubtedly alter the interactions of the virome with the host. However, little research has been done in all of these aspects other than limited descriptive studies to identify the presence or composition of the human virome. The NHLBI Microbiome Working Group in June 2014 clearly identified under-representation of studies of the human virome. Identification and characterization of unknown viral elements of the human virome and research on the interactions with the host will allow exploration of their impact on heart, lung and blood health and diseases, including impact in the presence of immunosuppression with the host such as in AIDS or HIV infection.

Feasibility and challenges of addressing this CQ or CC :

This initiative is feasible because of new technologies that have been developed recently such as the deep sequencing techniques. The initiative is also timely in that research supported by the NIH Human Microbiome Program and other programs has allowed us to better understand microbiome, especially bacteria in and on humans, and we began to realize the magnitude of the virome. This initiative will attract more investigators to not only identify more elements of the virome but more importantly to understand the roles of the human virome in heart, lung and blood health and diseases, and eventually to help develop diagnostic and intervention strategies.

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

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

Clinical Trials in Pediatric Sleep Disorders

Effect of anti-inflammatory medications (including nasal steroids and leukotriene antagonists) in children with obstructive sleep apnea syndrome, stratified for severity of OSAS as well as presence of atopy.

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 :

Small studies suggest a therapeutic effect of anti-inflammatory medication in childhood OSAS. This may be especially useful in children with residual OSAS following adenotonsillectomy (as CPAP adherence tends to be low) or children who are poor candidates for surgery. Current studies have been limited to children with extremely mild OSAS, have not determined whether atopy plays a role in the response to therapy, and have been limited to very short-term trials.

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

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Goal 2: Reduce Human Disease

Molecular effects of ischemia and reperfusion

What is the impact of total body ischemia and reperfusion on coagulation, inflammation, and endothelial function?

Submitted by (@rebecca.lehotzky)

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 : AHA Staff & Volunteers

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Goal 3: Advance Translational Research

Scientific priorities for HIV-related cardiovascular research

Millions of virally suppressed patients with HIV/AIDS survive to older ages and will become increasingly vulnerable to inflammation-associated cardiovascular disease. The critical challenge is to determine whether age-driven cardiovascular declines that occur HIV-infected people are exacerbated by the persistent systemic inflammatory drive that occurs in virally suppressed patients. Studies that document cardiovascular ...more »

Submitted by (@bgelman)

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 impact of this critical challenge would be to heighten the translational impact of HIV-related cardiovascular research. Key facets of this challenge are: 1) To give high priority to studies that use human tissue specimens that have been carefully annotated and biobanked, 2) To be certain that proposed studies employ tissue from age-appropriate comparison patients who were not HIV infected, and 3) To avoid giving undue credence to acute infection or in vitro infection models (as with tat and gp120 toxicology) that do not reflect immunologic and virologic mechanisms in virally suppressed patients. Millions of virally suppressed patients with HIV/AIDS survive to older ages, and become increasingly vulnerable to cardiovascular disease. Ischemia-related disease causes dysfunction especially in organs that depend on abundant blood flow such heart, brain and kidneys. All these organs are affected to some extent by persistent inflammation in virally suppressed HIV-infected patents. The compelling question/critical challenge is to determine whether age-associated cardiovascular changes are exacerbated by persistent mild systemic inflammatory drive that are found in blood vessels of virally suppressed patients. Studies that document the presence of cardiovascular changes in older infected people without controls, or in vitro models of acute infection, both do not address issues of high translational relevancy. Using human tissue specimens from age-appropriate controls does.

Feasibility and challenges of addressing this CQ or CC :

Feasibility:

1) Obtaining well-annotated organ specimens from HIV infected and noninfected people is feasible. The National NeuroAIDS Tissue Consortium (NNTC) collection goes well beyond the CNS and includes heart, lung, kidney, gut, liver, spleen and other organs. Many of the organs specimens in the collection have been annotated with virological and immunological markers already.

2) Over 900 autopsies on HIV infected patients are banked by the NNTC and over 100 of these decedents were over the age of 50. Over 200 controls are effectively banked. These specimens and related clinical data are in the public domain at this time.

3) Age appropriate autopsies were done by the NNTC, and a large number of NIA sponsored tissue repositories have accumulated tissue from elderly patients.

Challenges:

1) The limitations of using autopsy material and the limits of a cross sectional view need to be better understood and appreciated. These studies should not be written off scientifically as "observational" or "not hypothesis driven."

2) The lessons of not using age-appropriate controls have NOT yet been learned in the HIV/AIDS research community. A prime example is an overabundance of brain aging surveys in HIV infected populations that did not contain age-appropriate controls. A controversial and inconclusive brain aging pathology literature was produced because of that.

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

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