Genetics, epigenetics and physiological/morphological responses to environmental changes are - in general studied in isolation from each other. The fundamental goal of this project is to investigate the - question of phenotypic plasticity and its basis in genetics, epigenetics, population and environment - induced posttranscriptional modifications by a concomitant investigation of these fields and their impact - on fitness in a host-parasite system. S. mansoni and its invertebrate and vertebrate hosts provide a - excellent model since, as with all parasites, (co)evolution is rapid, but in contrast to other host-parasite - systems we observe here a pronounced phenotypic variability of the infective larvae. These phenotypes - are relatively stable within one generation, they can be characterized experimentally using molecular - markers and infection success can be measured quantitatively for each phenotype. Since, at the current - state of the art, it would be ambitious to deal with this topic exclusively by a combined wholegenome/ - transcriptome/proteome approach, we intend to begin with two groups/families of candidate - proteins: MSPP and Ag10-3. Both have similarities to the mucin group of proteins and we will refer - to them as mucin-like proteins. They are highly polymorphic molecules and their gene structure, - their organization in multi-gene families and their involvement in critical interactions with the immune - system of their hosts make them targets of choice for the development of studies on the - phenotype/genotype/epigenotype relationship that we propose to undertake. ...

Background - Parkinson’s disease (PD) is considered as being a multifactorial disease, resulting from the interplay of environmental factors and genetic susceptibility ; in particular, pesticides and genes involved in xenobiotic metabolism may play a role. The Mutualité Sociale Agricole (MSA) is the French health insurance system for farmers and workers connected to the agricultural world and offers a unique opportunity to study a population with a high prevalence of professional pesticide exposure. A previous case-control study of PD among MSA affiliates (TERRE) was carried out and pesticide exposure was assessed using an individual exposure assessment method by occupational health physicians. Objectives - As part of a larger program that aims at establishing a surveillance system of PD among MSA affiliates, our proposal is to carry out a community-based case-control study of PD in four MSA centers. Our objectives are (i) to study the relation between professional exposure to pesticides and PD using a period by region by crop by pesticide matrix ; (ii) to study the relation between PD and polymorphisms of genes involved in the detoxification of xenobiotics and neurodegeneration ; (iii) to study the interaction between pesticides exposure and polymorphisms of genes involved in the detoxification of xenobiotics ; (iv) to conduct a pilot study on the presence of Actinomycetes and Nocardia and the synthesis of proteasome inhibitors in the environment of a small number of cases and controls. Five teams will participate to this multidisciplinary study (Inserm U708 -Neuroepidemiology-, U490 -Molecular toxicology-, U508 -Epidemiology of chronic diseases : impact of gene-environment interactions- ; Mycology laboratory of the University of Lyon ; Département Santé-Travail of Institut de Veille Sanitaire). Methods and expected results- PD cases aged 18-80 years old will be recruited in four MSA centers (2006-2007). They will include prevalent cases (less than 10 years of disease course) and incident cases. They will be identified in computerized databases of requests for free health coverage for PD and antiparkinsonian drug use. Cases will be examined by a neurologist and PD diagnosis will be established using standardized criteria. We will randomly select two controls matched on sex, age, and center to each case among all subjects free of PD affiliated to the MSA. We expect to recruit a minimum number of 420 cases. Cases and controls will be interviewed to obtain detailed data for professional history and, if applicable, type of farming. We will combine the data obtained for each individual with a region by period by crop by pesticide matrix. We will use buccal swabs to collect DNA and carry out genetic studies of xenobiotic metabolism and neurodegeneration. The functionality of the polymorphic genes will be studied in different systems. The two case-control studies will be treated as independent studies and analyzed separately. We will compare the results obtained for the association between PD and genetic polymorphisms or pesticides (using two different methods of exposure assessment) and we will focus on replication of our findings for aims (i) to (iii). We will conduct a pilot study on the presence of Actinomycetes and Nocardia and the synthesis of proteasome inhibitors in the environment of cases and controls by taking samples from the soil of the farms for a random sample of 10 cases and 10 controls.