Cód. SSPA: IBiS-E-01
Research Lines
- Melatonin as a therapeutic tool in inflammatory pathologies. Applicability in the treatment of Multiple Sclerosis
This research line focuses on analyzing the immunomodulatory, anti-oxidant and neuroprotective effects of melatonin in Multiple Sclerosis (MS) and its preclinical model, Experimental Autoimmune Encephalomyelitis (EAE), as a basis for the development of neuroprotective therapies. Existing experimental evidence suggests that MS treatments should be based on a combination of anti-inflammatory, regenerative and neuroprotective strategies. In this line, melatonin, a molecule initially known for its synchronizing effects on physiological processes subject to circadian rhythms, such as the sleep/wake cycle, without toxicity and capable of crossing the blood-brain barrier, has been proposed as a possible treatment for MS due to its immunomodulatory, antioxidant and neuroprotective capacity.
Our research group has published the first study demonstrating that melatonin protects against EAE by decreasing immune infiltration in the central nervous system and specific Th1 and Th17 lymphocyte responses specific for myelin peptides, while increasing the regulatory T response and anti-inflammatory cytokine levels. We have also described that melatonin alters the expression of chemotactic, co-stimulatory and co-inhibitory molecules involved in the activation and polarization of T lymphocytes and in their attraction to the central nervous system as well as controlling the pro-inflammatory response in circulating leukocytes from MS patients. We have also described the synergistic effect of melatonin and corticosteroids in the control of EAE through immunomodulatory and neuroprotective mechanisms.
The data obtained have allowed us to obtain funding to lead a coordinated project with the aims of: a) evaluate the use of melatonin as a therapy for progressive MS by using the preclinical model of progressive MS; b) conduct a randomized, double-blind, controlled clinical trial to evaluate the safety and efficacy of the combined administration of melatonin and ocrelizumab in patients with primary progressive MS (MELATOMS-1 study; ClinicalTrials. gov: NCT03540485; EudraCT number: 2018-001779-18). The MELATOMS-1 study, led by our research group, is a multicenter clinical trial, authorized by the AEMPS in February 2019 that is currently ongoing. It is the first worldwide clinical trial with the aim to evaluate the combined use of melatonin and ocrelizumab in patients with primary progressive MS.
- Immunoendocrine actions of plant bioactive peptides. Generation of functional foods
There is a growing awareness of the importance of healthy nutrition, so the search for new food products that can not only provide balanced nutrients, but also beneficial health effects, has become the study of functional foods an emerging field.
In this way, our group has demonstrated that plant protein hydrolysates exhibit specific biological activities, in addition to their already established nutritional value. We have described anti-inflammatory and anti-oxidant effects of Lupinus angustifolius L. protein hydrolysates (LPHs), both in vitro and in vivo approaches. Likewise, we have observed that the administration of LPHs has lipid-lowering effects, decreases steatosis and visceral adiposity in hyper-cholesterolemic animals, and that the daily intake of a functional food based on LPHs reduced total cholesterol levels and LDL/HDL index in participants of the Lupine-1 study (clinical trial led by our group; ClinicalTrials. gov Identifier: NCT02590887), as well as having beneficial effects on their immune and oxidative status.
We are currently developing research projects aimed at assessing the effects of LPHs on the different components of obesity, such as adiposity, oxidative stress, inflammation, as well as metabolic fatty liver disease (MAFLD). We have recently obtained a competitive project whose main objective is to assess the combined effects of lupin biopeptides and melatonin on obesity and fatty liver disease associated metabolic dysfunction through a pre-clinical approach in animal models of obesity and the conduction of a clinical trial in obese patients with MAFLD (LupiMel Study).
- Development of molecular tools for the genetic diagnosis of rare diseases
The "omics" era has given rise to analytical systems are able to guide personalized care, giving explanation and shape to the idiosyncrasies of each individual, both in health and disease processes.
In the context of rare diseases, genetic conditions (single gene disorders and copy number variants) are the leading cause of morbidity and mortality. Many of these conditions are very rare (1: 50,000 to 1: 20,000 live births), but due to the large number of individual entities (approximately 8000 syndromes currently recognized according to OMIM: https://www.omim.org/ or Orphanet: https://www.orpha.net/consor/cgi-bin/index.php), the total number of individuals as a whole is considered a public health problem at the European level. These patients can go for years without an etiological diagnosis until massive sequencing of their exome and/or a CGH-array of SNPs are , which helps the clinician in their treatment, the families in the cessation of their uncertainty and the whole population as the different causes of disease are elucidated.
The most lethal genetic variants are usually "de novo", the first mutated member of a family being the patient in question (this is the case in 40% of cases), so that the genomic study of minority diseases with exome, CGHarray of SNPs and supporting transcriptomics, becomes an exciting field of research that goes hand in hand with clinical diagnosis (R+D+I).
- Implementation of circulating DNA technology in the diagnosis and follow-up of tumor pathology in childhood cancer and monitoring of solid organ transplantation
- - Childhood cancer
Cancer is a rare disease in children and adolescents, but it is still the leading cause of death from disease in children older than one year. The spectrum and frequency of somatic gene alterations in childhood cancer differentiate it from adult cancer and are not yet clearly defined. Knowledge of the spectrum of these mutations would provide us with better patient stratification, personalization of treatment and monitoring of treatment efficacy. The evaluation of this mutations in circulating DNA offers significant advantages over biopsy analysis, allowing a sensitive and non-invasive detection of low prevalence mutations and can be very useful in the detection of mutations in minority clones.
A few years ago our group established a relationship with the Pediatric Oncology Unit of the HUVR for the evaluation of possible mutations in both DNA and circulating tumor RNA by NGS to evaluate the tumor genotype and once the specific mutations are detected, monitor them by digital PCR in the patient's serum in a non-invasive way. To date, we have been able to fine-tune the necessary methodology and establish a coordinated action protocol, with very promising preliminary results.
- - Monitoring of solid organ transplantation
We have established the detection of circulating organ-specific DNA in the serum of the transplanted patient as a non-invasive, sensitive, specific and early genomic diagnostic marker in the diagnosis of acute cellular rejection after solid organ transplantation.
Currently, the gold standard in the confirmation of graft damage continues to be biopsy of the transplanted organ. However, this technique is invasive and risky.
Both acute and chronic rejection process, there is an associated apoptosis of specific cells of the transplanted organ, in this situation the specific DNA of the donated organ would be significantly increased.
Our group, in collaboration with the clinical units involved in both heart and liver transplantation has shown that there is a significant increase in circulating donor-specific DNA both at the time of biopsy-proven rejection and several days before rejection is diagnosed. These results point out to the possibility of including the detection of circulating donor-specific DNA as a non-invasive biomarker in transplant monitoring for possible early intervention that may eventually reduce the risk of rejection and transplant loss.
https://investigacion.us.es/sisius/sis_depgrupos.php?ct=&cs=&seltext=CTS-160&selfield=CodPAI
