Pathological plasticity of myocardium.
We are analysing the involvement of transforming growth factors beta (TGF-βs, activin and BMPs) in the molecular pathophysiology of myocardial remodelling secondary to haemodynamic stress and in altered development.
1. 1. Pathological plasticity of myocardium subjected to pressure overload. Aortic stenosis is the most frequent valvular cause for surgery in our area and is associated with a left ventricular hypertrophy which is a response of pathological significance in these patients. We are studying the molecular mechanisms of myocardial remodelling in this context using samples of myocardium of patients with aortic stenosis, a murine experimental model of this pathology and cell cultures.
1.2. Developmental variations and pathological plasticity of myocardium in Down syndrome.
The Ts65Dn mouse (trisomy of an area of chromosome 16 homologous to the human 21) is an experimental model of Down syndrome that reproduces its phenotypic characteristics. We are studying the involvement of the TGF-ß family in cardiac development variations found in this model.
2.Pathological plasticity of the aortic wall.
We are analysing the involvement of transforming growth factors beta in the molecular pathophysiology of the remodelling of the aortic wall in relation to aneurysm formation. Progressive dilation of the aorta carries high rates of morbidity and mortality. We are studying the role of TGF-ßs in the molecular pathophysiology of the pathological remodelling of the aortic wall in aneurysm formation. We intend to: 1) Establish signalling pathways involved in the vascular chronic inflammatory process responsible for progressive aortic dilatation; 2) Identify biomarkers to assess the risk of rupture and assist in surgery indication; and 3) Establish new therapeutic targets
3. Pathological plasticity in the central nervous system.
3.1 Pathological neuronal plasticity of the nociceptive system.
The mechanisms linking TGF- ßs and modulation of pain transmission, basally and in pathological plasticity models of the nociceptive system, are being analysed.
Chronic neuropathic pain is highly resistant to conventional drug treatment. We have demonstrated the involvement of the TGF-ß family in processing the physiological nociceptive signal. We intend to study: a) Molecular mechanisms involving TGF-ß in neuropathic pain, and experimental inflammatory pain; b) The interaction between TGF-ßs and the endogenous opioid system; c) The involvement of TGF-ßs in adaptive processes in chronic opioid therapy; d) The involvement of TGF-ßs in the hypoesthesia of experimental Down syndrome.
3.2. Pathological neuronal plasticity in learning and memory circuits.
We are analysing the mechanisms that connect the TGF-ß family with cognitive variations and neurodegenerative disease in Down syndrome.
Down syndrome causes more cases of mental retardation and all patients develop an Alzheimer-type neuropathology early on. Deficits in the synthesis and transport of trophic factors could mediate these variations. Furthermore, the TGF-ß family is involved in the pathophysiology of experimental Alzheimer’s disease. We intend to evaluate the role of TGF-ß in the cognitive variations found in the Ts65Dn mouse and evaluate different therapeutic strategies.