Research at the CRG

Research at the CRG

Alterations in skin formation

Principal Investigator: Vivek Malhotra

1 Introduction: what does this involve?
Collagen VII is a very large protein that is secreted by skin forming cells. Upon secretion, it assembles into long coiled-coiled cables that are necessary for attaching the epidermis to the dermis and therefore for skin formation.

2 Problem: what limits do we face today?
Patients with mutations in the collagen VII gene exhibit blisters in the skin and mucosal membranes (Epidermolysis Bullosa) and there is currently no known cure.

3 Solution: how can we improve this?
We have found the first intracellular receptor specific for collagen VII secretion. This discovery is important for the basic understanding of how bulky proteins such as collagens, in general, are secreted.

4 Impact: how will this impact society?
Our findings are also important for understanding how regulated collagen VII secretion is employed in skin biogenesis and therefore they provide a potential means for discovering novel therapeutics for the diseases collectively known as Epidermolysis Bullosa.

Progress in the neuronal regeneration of retinal tissue

Principal Investigator: Pia Cosma

1 Introduction: what does this involve?
There are currently different lines of research exploring the possibility of regenerating damaged tissue by stem cell reprogramming. One of these mechanisms is reprogramming through cell fusion. Since the first embryonic stem cells were obtained in the lab in 1998, scientists all around the world have been trying to use them to regenerate diseased organs and tissues. Despite this, the research has turned out to be more difficult than predicted, and up to now, results have been few and far between.

2 Problem: what limits do we face today?
When the retinal tissue deteriorates, this seriously affects a person’s quality of life, as the majority develop serious sight problems and a high percentage go blind. Retinal tissue is easy for scientists to access and it has a very weak immune response to transplanted cells, making it a good choice for study.

3 Solution: how can we improve this?
Using a specific type of stem cell, obtained from bone marrow, it has been possible to regenerate retina in mice. The fact that every subject has two eyes makes it easier to evaluate the efficacy and safety of the therapy by treating only one eye and comparing what happens in both.

4 Impact: how will this impact society?
Bone marrow stem cells can be fused with other cells, in this case retinal neurones, to regenerate the damaged tissue. The ultimate goal is to test this breakthrough on patients, to treat some of the commonest causes of blindness, like glaucoma, diabetic retinopathy, and retinitis pigmentosa. The discovery has been made in mice and the next step is to test it in pigs before, finally, being able to trial it on humans. To achieve this, the findings have been patented and an alliance has been set up with Ferrer Internacional, to develop a drug based on this technique. If everything goes well, it is hoped that clinical trials on patients will begin at the end of 2015.

Towards new therapies for lung cancer

Principal Investigator: Juan Valcárcel

1 Introduction: what does this involve?
We have identified a key regulatory step in the control of lung cancer cell proliferation.

2 Problem: what limits do we face today?
This step consists of a switch between two alternative products of the gene NUMB, which are generated by alternative RNA splicing. Depending on the direction of the switch, cells either actively proliferate or their divisions are halted. Importantly, mutations frequently identified in lung adenocarcinomas affect the alternative splicing of this gene and promote the switch towards cell multiplication.

3 Solution: how can we improve this?
By modulating this regulatory step, the proliferation of human lung cancer cells, grown either in tissue culture or as mouse xenografts, can be enhanced or inhibited using small-modified oligonucleotides.

4 Impact: how will this impact society?
This new class of alternative splicing modulators is currently used in clinical trials to target other genes for treating spinal muscular atrophy. We are currently working on an in-depth understanding of the molecular mechanisms underlying this alternative splicing switch, with the aim of generating improved reagents with therapeutic potential.