Genética de Doenças

Interesse da Investigação

My scientific interests are concerned with the understanding of the genetic basis of resistance/susceptibility to disease. The vast majority of common diseases studied to date have been shown to depend on multiple genetic factors. This is the case of several autoimmune and infectious diseases where the main challenge is now to reveal the contribution of individual genetic factors to the disease process. I am proposing to develop a research program based on the systematic analysis of individual genetic factors involved in disease resistance or disease susceptibility both in humans and in murine models. The diseases under study are primarily type 1 diabetes and malaria. The research program is based in 4 distinct but convergent perspectives: (1) mouse genetics, (2) human genetics, (3) statistical genetics and (4) bio-informatics. This program is supported in a technological platform aiming to include all the steps involved in formal disease gene isolation namely fine genetic mapping and candidate gene analysis.

Membros do Grupo

Luciana Moraes	Postdoc
	Tel: 21 446 4635
Nádia Duarte	Postdoc
	Tel: 21 446 4635
Riadh Ben Mansour	Postdoc
	Tel: 21 446 4635
Inês Rolim	Research Technician
	Tel: 21 446 4635
Lígia Deus	2005 PDIGC PhD Student
	Tel: 21 446 4635
Maria Do Rosário Sambo	2005 PDIGC PhD Student
	Tel: 21 446 4527
Joana Rodo	2006 PDIGC PhD Student
	Tel: 21 446 4635
Lurdes Duarte	2008 PGD PhD Student
	Tel: 21 446 4635
Elizabeth Ball	2008 PGD PhD Student
	Tel: 21 446 4514

Projecto de Investigação

Genetic determinants of resistance to hepatic infection in murine malaria models

This project aims to identify genetic factors that confer resistance to Plasmodium hepatic infection in mouse models. Unraveling the identity of genetic host factors controlling resistance to the hepatic stage of malaria is an important element to the understanding of malaria pathogenesis and may lead to the identification of naturally selected mechanisms of disease resistance. Little is known on host mechanisms able to mediate resistance to malaria infection at the liver stage. In fact, most studies on host genetic resistance are focused on malaria disease phenotypes like hyperparasitaemia, hemolytic anemia, reticulocytosis and cerebral malaria. By choosing the hepatic stage of the disease this project elects the liver as the target organ of investigation. This will offer clear advantages in the identification and evaluation of candidate resistance genes and is enabling the scrutiny of the individual liver cell types as mediators of the resistance mechanisms. The workplan entails the genetic mapping of liver resistance to malaria infection, proceeds through the fine genetic mapping by construction of congenic and subcongenic mouse strains, towards the identification of the positional candidate genes of malaria resistance. In addition, we will aim to isolate the cellular components of liver resistance and to test whether candidate genes are associated with the control of molecular pathways involved in liver response to infection. The project starts by the genetic analysis of a phenotype of liver resistance to infection by Plasmodium berghei, a parasite known to be highly pathogenic in the mouse.

Funding

POCI/IMI/61057/2004

Colaboradores

IMM
Maria Mota

Projecto de Investigação

Genetic analysis of response to toll ligands in the Non-Obese Diabetic mouse

The Non-Obese Diabetic (NOD) mouse spontaneously develops a form of autoimmune diabetes that closely resembles the human Type 1 diabetes (T1D). The disease is caused by an autoimmune reaction that targets the -cells in the pancreatic islets of Langerhans and leads to their progressive destruction and to overt diabetes. The autoimmune process is preceded by islet infiltration of mononuclear cells; an inflammatory process called insulitis. While the T cell compartment of the NOD mouse has been intensively studied, it is uncertain whether the NOD innate immune system plays a role in the development of diabetes. This project proposes a genetic approach to study the involvement of the innate immune system activities in the pathogenesis of the autoimmune process evolving in the NOD mouse. We will focus on the response linked to the toll-like receptors (TLR) in the cells of the innate system. We seek for phenotypes of abnormal TLR expression and altered cellular response to TLR ligands in the NOD mouse. Genetic analysis of such phenotypes will provide an etiological link to the disease. In addition, we will evaluate if absence of functional TLR response has an impact on diabetes incidence and insulitis severity. These results will shed light on innate mechanisms operating in the autoimmune process developing in the NOD mouse and will contribute to the dissection of the polygenic component of T1AD in the NOD mouse

Funding

POCI/SAU-MMO/62964/2004

Colaboradores

Umea University
Dan Holmberg

Projecto de Investigação

Generation of mouse models for pregnancy-associated malaria: pathology and immunological characterization

Every year at least 50 millions pregnant women are exposed to malaria infection leading to life threatening conditions for the mother and the developing fetus. Pregnancy-associated malaria (PAM) courses with parasite sequestration in the maternal placental with consequent maternal anemia, decreased fetal viability and infant low birth weight due to both prematurity and intra-uterine growth retardation. Although, PAM has recently attracted many research efforts, the specific pathologic bases for these outcomes are poorly understood and many difficulties are posed to study PAM in humans. This project aims to establish and analyze mouse models that show pathologic features of human PAM. This is initiated by characterizing the course of infection and placental pathology in different mouse strains. These pathology models will be used as tool to study gestational malaria and will offer opportunities to investigate the transplacental transmission of disease and vertical transmission of disease resistance.

Projecto de Investigação

Type 1 Diabetes: Associated immunopathology and genetic susceptibility

Immune mediated type 1 diabetes (T1AD) is a common disease of multifactorial nature. Although genetic susceptibility to T1AD has been attributed to a fairly high number of chromosomal regions, their pathogenic role is not understood and to date just three loci have been confirmed and considered as true diabetogenic factors (MHC, CTLA4 and INS). This proposal represents a multidisciplinary effort to study the genetic basis of the immunopathology associated to T1AD in the Portuguese population. Affected child families will be ascertained among recently diagnosed children/adolescents attending the major T1AD clinical services in the Lisbon region. This family collection will be investigated for compliance with the T1AD diagnosis criteria, for inheritance of impairments related to immunological functions and for frequency of autoimmune disorders concurrent with T1AD. In parallel, allele frequencies at T1AD susceptibility loci will be determined namely for HLA and CTLA4 genes. This project aims to collect data to test the hypothesis that organ-specific autoimmunity entails susceptibility genetic factors conferring general predisposition to autoimmunity. To this end, genetic association tests will be performed to search for genotypic combinations of T1AD susceptibility HLA and CTLA4 alleles, that control immuno-regulatory functions, patterns of auto-antibody occurrence and expression of immuno-mediator molecules. Furthermore, we will investigate the involvement of such genetic factors in the occurrence of other organ-specific autoimmune thyroiditis, celiac disease and multi-organ autoimmunity associated to T1AD. This work will contribute to elucidate the pathogenic mechanisms operated by the combination of genetic factors that confer susceptibility to T1AD and to evaluate their role in clinical, silent or undiscovered concurrent autoimmune disorders of T1AD patients in the Portuguese population.

Funding

POCTI/SAU-MMO/57995/2004

Colaboradores

Centro Histocompatibilidade do Sul
Rosário Sancho
Dário Ligeiro

Hospital D. Estefânia, Lisboa
Guilhermina Fonseca
Rosa Pina

Hospital de Santa Maria, Lisboa
Maria Manuela Madeira
Lurdes Sampaio

Associação Protectora dos Diabéticos de Portugal
José Manuel Boavida
Rui Duarte

Fac. Farmácia, Universidade de Lisboa
Manuela Catarino

Projecto de Investigação

Genetics of Human Malaria

The goal of this project to carry out fine genetic mapping of regions of the human genome to find genetic determinants affecting the disease and to determine the causal basis of associations between candidate genes polymorphisms and susceptibility to malaria. The projects unfolds in two levels:

1) A whole population-based study in the S. Tome Island. The epidemiological and clinical monitoring of a genetic and geographically isolated human population in the island of Principe provide an ideal scenario to identify host genetic factors that confer resistance to malaria, control the clinical course of the disease or affect the outcome of therapeutic interventions.
2) A case-control association study in Angola. This study will focus on Cerebral Malaria and is aimed to identify genetic factors conferring CM susceptibility as compared to other clinical forms of disease and to healthy controls.

Colaboradores

Centro Nacional de Endemias
S. Tomé e Príncipe

Publicações

(Selected) Update January (2009).

Nuno Sepúlveda, Carlos Daniel Paulino and Penha Gonçalves, C. (2009). Bayesian analysis of allelic penetrance models for complex binary traits. Computational Statistics & Data Analysis 53,4 :1271-1283

Côrte-Real J, Rodo J, Almeida P, Garcia J, Coutinho A, Demengeot J, Penha Gonçalves, C. (2009). Irf4 is a positional and functional candidate gene for the control of serum IgM levels in the mouse. Genes Immun 10(1) :93-9

Gonçalves LA, Almeida P , Mota MM, Penha Gonçalves, C. (2008). Malaria Liver Stage Susceptibility Locus Identified on Mouse Chromosome 17 by Congenic Mapping PLoS ONE 26;3(3) :e1874

Neres R, Marinho CR, Gonçalves LA, Catarino MB, Penha Gonçalves, C. (2008). Pregnancy Outcome and Placenta Pathology in Plasmodium berghei ANKA Infected Mice Reproduce the Pathogenesis of Severe Malaria in Pregnant Women PLoS ONE 13 :3(2)

Sepulveda N, Paulino CD, Carneiro J, Penha Gonçalves, C. (2007). Allelic penetrance approach as a tool to model two-locus interaction in complex binary traits Heredity 99(2) :173-84

Rodo J. and Penha Gonçalves, C, (2007). Autoimmunity imprinting: a pathogenic role for maternal autoantibodies Curr. Res. In Immunology 47 :58

Fernandes E, Pacheco A, Penha Gonçalves, C. (2007). Mapping of quantitative trait loci using the skew-normal distribution. J Zhejiang Univ Sci B 8(11) :792-801

Gonçalves LA, Vigário AM, Penha Gonçalves, C. (2007). Improved isolation of murine hepatocytes for in vitro malaria liver stage studies. Malar J 20;6 :169

Rodo J, Goncalves LA, Demengeot J, Coutinho A, Penha Gonçalves, C. (2006). MHC class II molecules control murine B cell responsiveness to lipopolysaccharide stimulation J Immunol 1;177(7) :4620-6

Monteiro MC, Couceiro S, Penha Gonçalves, C. Dec; (2005). The multigenic structure of the MHC locus contributes to positive selection efficiency: a role for MHC class II gene-specific restriction. Eur J Immunol 35(12): :3622-30