Transatlantic Networks 2010-2011

Four new Transatlantic Networks were selected for funding by the Scientific Advisory Committee at its meeting in April.  These four were chosen from among the 102 expressions of interest received by the Fondation Leducq last autumn and the 14 that went on to submit a full application.  The innovative projects hold much promise for improving our understanding of cardiovascular diseases.  The networks awarded funding in 2011 are:

1) Genomic, epigenomic and systems dissection of mechanisms underlying dilated cardiomyopathy

Coordinators:  Christine Seidman, Harvard Medical School Boston
Stuart Cook, Imperial College, London

Dilated cardiomyopathy (DCM) represents a group of diseases of the heart muscle in which the heart becomes enlarged and weakened. It is the most common cause of heart failure after ischemic cardiomyopathy, where there is heart muscle dysfunction because of an inadequate blood supply, such as with coronary artery disease.  Despite the clinical importance of DCM, its molecular basis remains poorly understood.

Drs. Cook and Seidman will lead their network, including seven other members from Austria, France, the United Kingdom and the United States, to apply state-of-the-art techniques to determine the genetic and mechanistic pathways of DCM.  They will identify genetic mutations in patients with DCM using both genome-wide association approaches and the latest DNA sequencing techniques; early results from such efforts have already uncovered a wealth of new information.  The network will then determine the mechanisms by which the identified mutations cause DCM in fruit fly, zebrafish, mouse and rat models, and in human heart tissue.  These studies will include the effects of the mutations on physiologic parameters like muscle cell contractility and electrical stability.

It is known that two patients with the same genetic mutation may have very different manifestations of DCM.  For this reason, the network will also study differences in gene expression patterns caused by mechanisms other than variations in the DNA  sequence (epigenetics). 

In summary, this network brings together world-class investigators with well-characterized patient cohorts, large DNA and tissue repositories, and expertise in genomics, cross-species models, and systems-level informatics to address a challenging clinical problem.  Ultimately, the investigators hope that their findings in DCM will provide important mechanistic and therapeutic insight for all causes of heart failure.

2) Translating human pluripotent stem cells from heart disease models to cardiac repair

Coordinators:  Andre Terzic, Mayo Clinic, Rochester
Michel Puc
éat, INSERM, Evry

Despite advances in treatment, heart failure remains a leading cause of hospitalization and death worldwide.  There are numerous conditions that can lead to heart failure, but the fundamental common problem is a loss of healthy, functioning cardiac muscle cells, which the heart is unable to replace due to its limited regenerative capacity.  Providing new healthy cells is therefore a therapeutic strategy, now being actively pursued around the world.

There are three broad categories of cells that may regenerate heart muscle cells:  embryonic stem cells, induced pluripotent stem cells, and reprogrammed adult cardiac cells.  These categories of cells vary in their degree of pluripotency, or their capacity to differentiate into various cell types.  At one end of the spectrum, embryonic stem cells have essentially limitless potential to become any kind of cell in the body.  Induced pluripotent stem cells are adult cells, such as skin cells, that have been manipulated to force the expression of genes necessary for stem cell properties.  Finally, the strategy of reprogramming adult cardiac cells seeks to augment the regenerative capacity of cells that already have properties of cardiac muscle.

Drs. Terzic and Pucéat, along with seven other colleagues from France, the Netherlands, the United Kingdom and the United States, will determine the effectiveness of these different cell populations as treatments for heart failure.  The network will delineate the genetic, epigenetic, metabolic, and physiologic properties of the different cell types, and determine the molecular signals that push them towards becoming cardiac muscle cells.  The network will make use of special expertise in cell-delivery approaches to maximize cell survival and integration into the heart; in strategies to protect the cells from harmful immunologic responses; and in minimally invasive techniques to track the fate of the cells in living animals.  Finally, the network will create induced pluripotent stem cells from patients with heart failure to better comprehend the obstacles to their therapeutic capacity, such as the effect of aged mitochondria (cellular compartments that produce the energy supply for the cell).

3) Lymph vessels in obesity and cardiovascular disease

Coordinators:  Mark Kahn, University of Pennsylvania, Philadelphia
Kari Alitalo, University of Helsinki

Blood vessels deliver nutrients and oxygen to tissues.  Lymph fluid, which is pushed out of blood vessels and bathes the tissues, is drained by lymph vessels that transport the fluid from the tissues back into the cardiovascular system.  In addition to maintaining tissue fluid balance, lymph vessels absorb ingested fats from the intestines and coordinate immune and inflammation responses.  There is crosstalk between lymph vessels and fat (adipose) tissue, suggesting a possible link between lymph vessel dysfunction, obesity and inflammation.  Lymph vessels are also located in the outer layer (adventitia) of large arteries, where their dysfunction may be important in arterial pathologies such as atherosclerosis and thrombosis. 

The largely unexplored relationship between lymph vessels, obesity and cardiovascular disease is the focus of this network of nine total members from Finland, Germany, Switzerland and the United States, led by Drs. Kahn and Alitalo.  The network will study mouse models and human patients to determine the molecular and cellular mechanisms by which lymph vessel dysfunction leads to disease.  For instance, investigators will study how lymph vessels and fat cells communicate with each other; how lymph fluid modulates fat cell growth and activity; how fat cells react to inflammation mediated through lymph vessels; and how lymph vessel dysfunction modifies metabolic traits in patients.  The network will determine whether lymph vessels represent a beneficial exit route for lipids and inflammatory cells from atherosclerotic plaques; whether the cells that line the interior surface of lymph vessels, like those of blood vessels, can regulate platelet activity and clot formation; and whether manipulation of the lymph vessel growth could be beneficial in heart failure.

The network unites leading laboratories in lymph vessel biology to find novel approaches to the prevention and treatment of obesity and cardiovascular disease.

4) Proteotoxicity: an unappreciated mechanism of heart disease and its potential for novel therapeutics

Coordinators:  Jeffrey Robbins, Cincinnati Children's Hospital
Mathias Gautel, King's College, London

Like skeletal muscle, cardiac muscle has the remarkable ability to adapt quickly to changes in workload and stimulation.  This adaptation is accomplished by changes in muscle cell contractility, electric behavior, metabolism, and growth.  More fundamentally, these changes result from alterations in gene expression, protein synthesis, and protein breakdown.  Indeed, maintaining an appropriate balance between protein formation and breakdown is important for the normal function and adaptation of cardiac muscle cells.  Many inherited cardiac diseases are caused by mutations in cardiac muscle proteins, and many environmental stresses can lead to errors in protein formation.   In both cases, the abnormalities may adversely affect protein function and turnover.  It is now emerging that failure to break down or clear proteins can result in proteotoxicity, a potential factor leading to inherited and acquired cardiac muscle diseases. 

The network aims to define how defects in the two major pathways of protein breakdown, (the autophagy-lysosomal pathway and the ubiquitin-proteasome system), can lead to the buildup in cardiac muscle cells of unneeded or misfolded proteins and, ultimately, heart failure.  Using mouse and rabbit models and human tissue samples, Drs. Robbins and Gautel and six other network members from Germany, Italy, the United Kingdom and the United States will determine the role of proteotoxicity in genetic and non-genetic forms of heart failure; dissect out the genetic and signaling networks that regulate the two protein breakdown pathways; and search for targeted therapies that reduce or block proteotoxicity in the hopes of developing new clinical treatments for heart failure.

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