Serono Research Grants, 2006

Field of Multiple Sclerosis Clinical Research

Research Project:

Implication of regulatory T-cells and the associated Foxp3, LAG-3, GITR, and OX40 genes in Multiple Sclerosis.

Main researcher:

Dr. Txomin Arbizu Urdiaín

Project Summary:

Main objective: To determine the usefulness of monitoring T cell regulators (Treg)
(CD4+CD25+ L-CD4+CD25++) as a predictive element of the appearance of short
term attacks, early residual disability and the clinical evolution of MS. It is hoped to
identify, in the first place, a decrease in the quantity and/or reactivity of the Treg in
patients with MS.

Methodology: It is anticipated to include 3 patient groups. 1- MS with a high number of active lesions. 2- Recently diagnosed MS. 3- cross-sectional group of the three
evolutionary forms (RR, SP, PP). Blood samples will be obtained in routine weekly
monitoring or in monthly follow up depending on the cohort.

The samples will be analysed at molecular and cellular level. It is hoped to quantify the expression of FoxP3, LAG-3, GITR, OX40 and CD152 in peripheral blood using quantitative real time RT-PCR, normalised for B2m, B-actin, G6PDH and GAPDH. Flow cytometry will also be used to determine the quantity of CD4+CD28+CD25+ (non-naive Treg) and CD152 and HLA-DR markers, also in T CD8+ cells, B cells (CD19, CD152 and HLA-DR). The functionality of each cell subtype will be determined.

Expected Results: The quantification of the Treg and the expression of genes such as FoxP3, LAG-3, GITR, OX40 and CD152 could be prognostic factors. We hope to confirm that the functionality of Treg decreases before the appearance of an attack and its possible relationship with the early appearance of residual disability. This momentary hypofunction will be greater in RR forms than in SP and PP forms. These results could be of great use in the design of therapeutic strategies adapted to each patient.

Jury:

Field of Clinical Research in Endocrinology

Research Project:

Quantitative analysis of the genes associated with metabolic syndrome and inflammation of intra-abdominal adipose tissue in prepubertal children.

Main researcher:

Dr. Ramón Cañete Estrada

Project Summary:

Obesity is a complex and multifactorial chronic disease which frequently starts in childhood and adolescence. In Spain, the prevalence on childhood obesity has increased dramatically from 4.9% in 1985 to 13.9% in 2000. Cohort and family studies have confirmed that heredability of the obese phenotype is very high. Likewise, there are a number of epidemiological evidences and cause relationships between obesity in youngs and the early onset of insulin resitance, metabilic syndrome (MS) and diabetes mellitus type 2, as well as increased risk of cardiovascular disease (CDV) and other alterations.

Genetic and environmental causes of changes in specific variables associated to early onset of insulin resistance and MS in infancy are largely unknown. Moreover, the realationships between characteristic parameters of MS and biomarkers of inflammation and CDV risk, and their influence on adult obesity and its comorbidities are also unknown.

The aim of the present project is to quantify and validate, using real time RT-PCR, the expression of genes related to MS and inflammation in prepubertal obese children. Selection of candidate genes will be based on previous results obtained by our group analysing differential gene expression in intraabdominal adipose tissue in obese and normal weight children as well as using th einternational data base of Gene Obesity Map.

Jury:

Field of Clinical Research in Infertility and Assisted Human Reproduction Techniques

Research Project:

Genetic Aetiology of premature ovarian failure (POF) and its association with fragile X syndrome: A study of POF 1 locus.

Main researcher:

Dra. María Isabel Tejada Mínguez

Project Summary:

Introduction: Premature ovarian failure or POF is defined as the presence of amenorrhoea with FSH levels in the menopausal range for women less than 40 years who previously had menstrual cycles. Fragile X syndrome (SXF) is due to the absence of a protein derived from the methylation of the FMR1 gene when the GGG triplet is abnormally expanded. Although premutated individuals (without methylation) should not have clinical symptoms, some premutated women have POF, which at the present time it is not known why. Very recently, the genomic region responsible for normal ovarian function between Xq26 and Xq28, that is to say, in the same region where the FMR1 gene is situated, is being investigated.

Objectives: 1) To study the whole Xq26 and Xq28 region, including the premutation of the FMR1 gene, to find out how many molecular mechanisms there are in the aetiology of POF in women with no history of RM. 2) To establish the relationships between all the molecular anomalies found (genotype) that appear in the zone with clinical symptoms (phenotype), with the aim of improving genetic assessment and reproduction. 3) To shed light on the possible pharmacological applications in the framework of individualised medicine for the ovarian stimulation of these patients.

Setting and study subjects: We will establish three groups of women for a better correlation: 1) Study group: 50 women with POF with no history of RM. 2) 50 women premutated by SXF with or without POF as Fragile X controls and 3) another 50 women without POF or SXF as controls.

Methodology: 1) Clinical studies (gynaecological and hormonal) of women patients older than 35 years in the three groups mentioned. 2) Molecular studies in the Xq26 and Xq28 region; Southern blot of FMR1 and its methylation; FISH with subtelomeric probes and MPLA “a la carte”. 3) Biostatistics and correlation studies on all data.

Jury:

Field of Clinical Research in Psoriasis

Research Project:

Role of IL-17 in the interaction of innate and acquired immunity in psoriasis

Main researcher:

Dra. Ana María Giménez Arnau

Project Summary:

Both innate and acquired immunity are involved in the pathogenesis of psoriasis. The efficacy of different treatments blocking TNF-a supports the role of innate immunity in psoriasis. Specific treatments targeting acquired immunity, such as cyclosporine A, anti-LFA-1 antibody and alefacept, are also effective. There seems to exist a connection between both types of responses in psoriasis. The exact mechanisms leading to this interaction are poorly characterised. Interleukin (IL)17 is a cytokine produced by memory T lymphocytes, capable of triggering innate immune response in different cells, such as fibroblasts, keratinocytes, endothelial cells and macrophages through cytokines, chemokines and natural antibicrobial peptids. IL-17 is present in psoriatic lesions, mainly produced by CLA+ T lymphocytes. Skin culture of bipsies of psoriatic lesions is a useful method for studying th eeffect of exogenous agents, for instance, antibodies, low molecular weight molecules or cytokines, can be analyzed by immunohistochemisty o gene expression. The aim of th estudy is to characterise the effects of IL-17 on biopsies from psoriatic plaques in vitro, by "gene array" The most relevant genes induced by IL-17 will be identified, and the results will be confirmed by RT-PCR, ELISA, inmunohistochemical studies and/or western blot.

Jury:

Bolsa Serono de Investigaçâo Clínica em Esclerose Múltipla

Research Project:

Expression of peroxisome proliferator activator receptors in circulating leucocytes of patients with multiple sclerosis.

Main researcher:

Dr. D. Armando Sena

Project Summary:

The purpose of this project is to research the impression of activator receptors of the proliferators of peroxisomes in leukocytes circulating in patients with definitive multiple sclerosis (MS) and isolated clinical syndrome. There are solid scientific foundations, including in experimental MS models, involving this type of receptors in the modulation of neuroinflammatory and neurodegenerative processes. In all, to date, there is no direct information obtained from these patients, to involve these receptors in the pathogenesis of the disease. This study aims to research this hypothesis and correlate the analysis of these receptors with the activity and evolution of MS, inflammatory markers and lipoproteic metabolism. This project may contribute to a better understanding of the disease and open new relational assessment means and therapeutic intervention.

Jury: