A SYSTEMS BIOLOGY APPROACH TO UNDERSTANDING THE MOLECULAR PATHOGENESIS OF CHRONIC LIVER DISEASES PROGRESSION

Project proposal title: A SYSTEMS BIOLOGY APPROACH TO UNDERSTANDING THE MOLECULAR PATHOGENESIS OF CHRONIC LIVER DISEASE PROGRESSION

Principal investigator (coordinator) (name and institution): Pere Ginès. IDIBAPS.

Co-principal investigator (name and institution): Patrick Aloy. IRB Barcelona

Liver cirrhosis is the 12th cause of death worldwide and is a progressive and irreversible disease without effective therapy.

Objective: To investigate the molecular pathogenesis of cirrhosis through the development of a computational liver model aimed at identifying key molecular points for disease progression

Methods: 

  1. Assessment of molecular pathways by performing transcriptome analysis from liver biopsies of patients at different disease stages; 
  2. Development of a computational liver model based on transcriptomic data, using a systems biology approach, with the objective of identifying key points of intervention in intrahepatic molecular pathways; 
  3. Validation of points of intervention. 
RESPIRATORY MICROBIOME AND COPD EXACERBATIONS

Project proposal title: RESPIRATORY MICROBIOME AND COPD EXACERBATIONS

Principal investigator (coordinator) (name and institution): Dr. Agustí (IDIBAPS) 

Co-principal investigator (name and institution): Dr. Gabaldón (CRG) 

Chronic Obstructive Pulmonary Disease (COPD) is a prevalent disease (10% of the adult population) whose incidence is on the rise (it currently is the 3rd cause of death globally). Some, but not all, COPD patients often suffer frequent episodes of exacerbation (ECOPD) of unclear origin, that impact negatively their prognosis and well-being and cause a huge economic toll. This project seeks to investigate the role of the pulmonary microbiome in ECOPD, by comparing it in 50 patients with (FE) and without (NE) frequent ECOPD (as well as with 50 healthy non-smoker controls). Microbiome quantification will be performed using next-generation sequencing of microbial rRNA regions in different pulmonary and extra-pulmonary compartments (BAL, sputum and feces). To asses the immune status of the host, we will determine mRNA transcriptome and the concentration of soluble immune mediators in blood and Brochoalveolar lavage (BAL) samples. The integration of results will be performed using network analysis. This project has the potential to uncover clinically relevant mechanisms of ECOPD and to identify novel therapeutic targets.

SPLICING FACTOR MUTATIONS IN HEMATOLOGICAL MALIGNANCIES

Project proposal title: SPLICING FACTOR MUTATIONS IN HEMATOLOGICAL MALIGNANCIES

Principal investigator (coordinator) (name and institution): Dolors Colomer (IDIBAPS)

Co-principal investigator (name and institution): Juan Valcárcel (CRG)

The groups of Dolors Colomer and Juan Valcárcel are already actively collaborating to study the impact of pre-mRNA splicing in the pathogenesis of -and potential therapies for- Chronic Lymphocytic Leukemia (CLL). The goal of the PhD project is to integrate clinical and molecular data to evaluate the antitumor activity of spliceosome modulators in in vitro and animal models of CLL, its dependence on the mutational status of splicing factors and the possibilities to combine these with other chemotherapies. The final aim is to identify key transcriptome changes and splicing regulatory mechanisms that can explain the pathogenic effects of splicing mutations and the therapeutic effects of drugs, as the basis for improved and personalized treatments.

BRCA1-DEPENDENT MOLECULAR AND CELLULAR MECHANISMS IN OVARIAN CANCER

Project proposal title: BRCA1-DEPENDENT MOLECULAR AND CELLULAR MECHANISMS IN OVARIAN CANCER 

Principal investigator (coordinator) (name and institution): Dr. Santamaria (VHIR)

Co-principal investigator (name and institution): Dr. Eduard Sabidó (CRG)

Ovarian cancer (OC) is the leading cause of death from gynaecological malignancies. For women carrying a mutant BRCA1 gene, there is a nearly 40% chance of developing ovarian cancer. In addition, patients with loss of function of BRCA exhibit greater resistance to current chemotherapy strategies and alternative therapies are needed to treat these patients. Therefore, developing new-targeted therapies that account for the genetic profile of patients will help improving the effectiveness of treatments and overcoming chemoresistance. We are currently investigating the beneficial effect of inhibiting the mitotic kinase PLK1, overexpressed in OC and associated with poor prognosis, and functionally related to BRCA1. Building up on this work, the present proposal aims to unravel the BRCA1 interactome and potential BRCA1 and Plk1 substrates underlying the BRCA1 key tumor suppressor function. Identifying new partners and linking Plk1 with the BRCA1-oncogenic signaling will likely allow us to discover new biomarkers and will therefore lead to the identification of new and more specific therapeutic targets.

NOVEL TARGETS TO PREVENT KIDNEY FAILURE IN DENT'S PATIENTS

Project proposal title: NOVEL TARGETS TO PREVENT KIDNEY FAILURE IN DENT'S PATIENTS 

Principal investigator (coordinator) (name and institution): Dr. Meseguer (VHIR)

Co-principal investigator (name and institution): Dr. Malhotra (CRG)

Dent disease, a rare X-linked inherited disorder, is a proximal renal tubulopathy characterized by low-molecular-weight proteinuria, hypercalciuria and nephrocalcinosis that progresses to renal failure and fibrosis. We postulate that beyond the known functional effects of mutations in the ClC5 gene, there are mutation-associated pathways and mechanisms to be discovered regarding proximal tubule cell function, that might better explain the (individual and familial) variability of the phenotype of Dent’s disease and the progression to fibrosis and end stage renal disease. Discovery of new genes and mechanisms relevant for proximal tubule function and, potentially, for the endosome-lysosome function, will lead to a better understanding of the fundamental processes affecting epithelial cell differentiation, regulation of transport mechanisms and role of tubular cells in renal disease progression; therefore providing with novel biomarkers and potential therapeutic targets for this disease.

CLINICAL DECISION SYSTEM FOR CANCER PATIENTS

Project proposal title: CLINICAL DECISION SYSTEM FOR CANCER PATIENTS 

Principal investigator (coordinator) (name and institution): Dr. Campo (IDIBAPS)

Co-principal investigator (name and institution): Dr. Gut (CNAG)

Decisions on the treatment of cancer patients are becoming increasingly more complicated and difficult. This is due to the dramatical increase of treatment options, the possibility to combine treatment regimes across the course of the disease and in function of response, and the amount of data that can be generated for one patient in preparation for treatment. In this project (thesis) a database will be constructed that acts a decision support system for clinical decisions and will capture longitudinal information on a patient over the course of the disease. The project will concentrate on lymphoid neoplasms as we already have a large body of information available to us that we generated through the ICGC CLL project and other collaborative in projects in hemato-oncology.

SYSTEMS VACCINOLOGY TO GUIDE EFFECTIVE AND SAFE HIV THERAPEUTIC VACCINES

Project proposal title: SYSTEMS VACCINOLOGY TO GUIDE EFFECTIVE AND SAFE HIV THERAPEUTIC VACCINES

Principal investigator (coordinator) (name and institution): Dr. García and Dr. Arnedo (IDIBAPS)

Co-principal investigator (name and institution): Dr. Aloy (IRB Barcelona)​

HIV has to date caused a pandemic with 35 million people infected with 1.5 million deaths yearly. Combined antiretroviral treatment (cART ) may stop progression to AIDS, but is not able to cure chronic HIV infection. Therefore, alternatives including therapeutic vaccination as immunotherapy are needed. The aim of the proposal is to develop and apply systems medicine approaches to identify molecular signatures induced early after therapeutic HIC vaccination that correlate with vaccine induced immune responses and to validate their potential to accurately predict viral suppression after cART interruption. To achieve this aim, this project will profile mRNA and microRNA expression and generate full proteome CTL epitope maps as readouts of the immune response during a dendritic cell-based vaccination strategy in HIV-infected individuals. Using different methods including predictive mathematical modeling, gene set analysis, network analysis, and deconvolution of cell populations, the rRNA microRNA and CTL profiles will be integrated with existing laboratory results and clinical readouts to define signatures of protective immunity. In particular, samples from the Dendritic Cell Vaccine (DCV-2) trial in Hospital Clínic Barcelona will be used as sustained viral suppression was observed in most vaccines, but not in placebo controls. Validation of the findings from our integrated analysis of DC vaccination analysis will be carried out with samples from a novel HIV immunotherapy trial, the IHIVARNA trial. This project will allow evaluation of the predictive value of this analysis for immunotherapy efficacy and the potential of individual parameters for treatment interruption as a personalized medicine approach.

IN VITRO SPERMATOGENESIS AS MODEL SYSTEM TO STUDY...

Project proposal title: IN VITRO SPERMATOGENESIS AS MODEL SYSTEM TO STUDY HUMAN SPERM DEVELOPMENT AND FERTILITY DISORDERS

Principal investigator (coordinator) (name and institution): Bernhard Payer (CRG​)

Co-principal investigator (name and institution): Rafael Oliva Virgili (IDIBAPS)​

Over 10% of couples suffer from infertility with about equal male and female contribution. The desire of having children late in life and environmental toxins led to an increase of problems and assisted reproduction is becoming common place. Little Is known about the underlying mechanisms of fertility disorders, due to the infeasibility to study normal and diseased human gamete development in vivo. Therefore in vitro systems of human egg and sperm development would greatly aid to advance our knowledge.

Here we propose to develop an in vitro system for sperm maturation from human induced pluripotent stem cells (hiPSCs) and to compare its epigenetic characteristics with that of normal sperm. A main goal will be to assess the completeness of histone replacement with protamines and the retention of specific histone marks at developmental genes in sperm chromatin. This Important late event in sperm development can be used to assess the in vivo--‐like quality of sperm derived from hiPSCs in vitro and will be the basis for research on its link to male fertility disorders. 

ADVANCES IN IDIOPATHIC INFLAMMATORY MYOPATHIES

Project proposal title: ADVANCES IN IDIOPATHIC INFLAMMATORY MYOPATHIES 

Principal investigator (coordinator) (name and institution): Dr. Grau (IDIBAPS)

Co-principal investigator (name and institution): Dr. Zorzano (IRB Barcelona) 

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of autoimmune diseases that comprise dermatomyositis (DM), polymyositis (PM), immune-mediated necrotizing myopathies (IMNM), and sporadic inclusion body myositis (sIBM). Several reports have studied the association between primary biliary cirrhosis (PBC) and IIM. Among these studies one has suggested that patients diagnosed with IIM who have the antimitochondrial antibody M2 (AMA2) could constitute a different clinico-pathological subgroup. PBC is an autoimmune disease characterized by the presence of AMA2 directed at the lipoic domain in the E2 pyruvate dehydrogenase complex sub-unit. Fatigue can be found among the clinical manifestations of PBC, affecting up to 50% of patients. In the present is work we intend to search for AMA2 in a large series of IIM patients in order to clarify their clinical and pathological characteristics. On the other hand, patients with PBC who show either prominent fatigue or weakness will be studied by means of muscle biopsy as well as functional analysis of mitochondria (pyruvate dehydrogenase complex activity). As a complementary test the behaviour of serum muscle enzymes such as creatinine kinase (CK) and aldolase over time will be evaluated as will the correlation between muscle MRI and muscle pathology. Finally, muscle involvement in patients with systemic sclerosis (SSc) will be studied.

MOLECULAR DETERMINANTS OF SENSITIVITY TO IMMUNE CHECK-POINT INHIBITORS (CPI) IN COMBINATION WITH...

Project proposal title: MOLECULAR DETERMINANTS OF SENSITIVITY TO IMMUNE CHECK-POINT INHIBITORS (CPI) IN COMBINATION WITH A HETEROLOGOUS LYSATE DENDRITIC CELL VACCINE (HLDC) IN MICROSATELLITE STABLE (MSS) COLORECTAL CANCER  

Principal investigator (coordinator) (name and institution): Dr. Maurel (IDIBAPS)

Co-principal investigator (name and institution): Dr. Ossowski (CRG) 

Cancers that have a low mutational load such as MSS colorectal cancer (mCRC) have poor responses to CPI and require additional approaches. We propose a prospective clinical trial to assess the efficacy of CPI associated to HLDC and an evaluation of an immunologic signature to predict efficacy in mCRC.

MULTIPLE SYSTEM ATROPHY: SYNUCLEIN REGULATION AND BIOMARKERS...

Project proposal title: MULTIPLE SYSTEM ATROPHY: SYNUCLEIN REGULATION AND BIOMARKERS DISCOVERY  

Principal investigator (coordinator) (name and institution): Dr. Tartaglia (CRG)

Co-principal investigator (name and institution): Dr. Martí (IDIBAPS) 

Multiple system atrophy (MSA) is a fatal neurodegenerative disorder associated with motor impairment and autonomic failure. Its defining neuropathological feature is the presence of glial cytoplasmic inclusions (GCIs) in oligodendroglia, formed by fibrillar alpha-synuclein protein. Yet the clinical and neuropathogical characterization of MSA is incomplete, disease-specific biomarkers are lacking, and pathophysiology remains largely unknown. The candidate will participate in an on-going collaboration between IDIBAPS (Dr. Martí) and CRG (Dr. Tartaglia) that aims to unravel regulatory factors of alpha-synuclein and MSA biomarkers. The work is designed to combine clinical assessment with experimental and in silico work.