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.

Hemophilia A is a rare X chromosome-linked recessive disorder that concerns 1/5000 individual. Genetic abnormalities in the FVIII gene result in qualitative or quantitative defects in FVIII production. In its severe form, hemophilia A is a life-threatening, crippling hemorrhagic disease. Treatment of hemophilia patients with therapeutic FVIII results, in up to 30% of the cases, in the emergence of anti-FVIII antibodies (inhibitors) that neutralize the pro-coagulant activity of the therapeutically administered FVIII. The development of FVIII inhibitors represents a major medical hurdle and a critical societal concern. In developed countries, cost of care of patients with inhibitors may reach 200 K€/year. In the last two decades, basic research on the allo-immunisation against FVIII has focused almost exclusively on characterizing the effector arm of the anti-FVIII immune response: the nature and mechanisms of action of FVIII inhibitors, and on deciphering the role of CD4+ T lymphocytes in the process. However, not much is known regarding the nature of the endocytic receptors involved in uptake and presentation of FVIII to CD4+ T cells by professional antigen presenting cells (APCs), which is the very first step in the initiation of deleterious allo-immune responses. We have recently demonstrated that human dendritic cells (DCs), the major professional APCs endocytose FVIII and present FVIII-derived peptide in the context of HLA-DR for the activation of FVIII-specific CD4+T cells. The working hypothesis in the first aim of my project is that a restricted set of endocytic receptors on APCs is responsible for the uptake of FVIII and its subsequent presentation to CD4+ T cells. We will thus identify the receptors implicated in FVIII endocytosis by APCs, using human monocyte-derived DCs and circulating human myeloid DC subsets such as BDCA-1+ and BDCA-3+ myeloid DCs as model APCs. Further, we will also explore the role of plasmacytoid DCs and of type I interferons on the level of expression of endocytic receptors on myeloid DC and in eliciting FVIII immune response. A corollary to our hypothesis is that blocking the interaction of FVIII with endocytic receptors on DCs will reduce FVIII uptake and hence prevent or delay the initiation of allo-immune response to exogenous FVIII in multitransfused hemophilia A patients. Based on FVIII structure, available literature and our preliminary observations, candidate endocytic receptors may belong to receptors for N-linked glycosylations. Using FVIII knock-out and/or endocytic receptor knock-out murine model, we will delineate in vivo the therapeutic relevance of interfering endocytic receptors on DCs to block anti-FVIII immune response. The identification of the endocytic receptors on APCs involved in FVIII endocytosis carries an enormous potential for the delineation of novel therapeutic strategies, based on either cellular/receptor or drug-mediated intervention. The expected results should provide explanations for the yet unexplained elevated immunogenicity of FVIII and provide new tools to modulate the interaction of FVIII with APCs. Furthermore, in the second aim I propose that monitoring the levels of the candidate endocytic receptors, either on the surface of circulating APCs, at the mRNA level or in their soluble form in the plasma, should be of important prognostic value for detecting patients at risk of developing FVIII inhibitors, and thus assisting clinicians in choosing for therapies alternative to FVIII administration. Importantly, because most of the patients with severe hemophilia A develop FVIII inhibitors in infancy, preventing or delaying the onset of the anti-FVIII allo-immune response will have dramatic repercussions in improving the clinical management and quality of life of the patients.

Many epidemiological studies have shown that low socioeconomic status individuals exhibit a higher prevalence of cardiovascular risk factors (such as smoking or low physical activity), and an increased incidence of and mortality from cardiovascular diseases. It is now recognized that an important perspective of research is to investigate the effects that the social characteristics of the residential context may have on cardiovascular health. Preliminary evidence indicates that people residing in socially deprived neighbourhoods have an increased risk of coronary mortality, beyond effects associated with individual factors. However, this literature has remained underdeveloped in France. Moreover, contextual studies exhibit important limitations: (a) most studies have not used the appropriate spatial analytic techniques allowing one to describe precisely the spatial distribution of cardiovascular diseases; (b) they have relied on cross-sectional rather than longitudinal data; (c) they have often only considered effects of the socioeconomic status of the context, neglecting other dimensions of the environment of residence; (d) they have defined the residential context using arbitrary administrative areas; (e) they have not investigated the mediating processes through which contextual factors may have an impact on cardiovascular health. In our past work, we have identified geographic variations in ischemic heart disease, though larger for mortality than for incidence. After individual-level adjustment, we found that geographic variations identified within large territories (such as a whole region) were related to population density, whereas spatial variations observed within urban areas were related to the neighbourhood socioeconomic status. Using French and Swedish data, we aim to better understand the processes leading to these observed spatial patterns of variations. Relying on inputs of sociology, geography, statistics, and epidemiology, we aim: (A) to increase our knowledge in the spatial distribution of cardiovascular morbidity and mortality; (B) to investigate the effects of the characteristics of the context on cardiovascular health by examining 1) what dimensions of the residential context are influent (population density, socioeconomic level, residential stability, social capital), 2) on what scales those contextual effects operate, 3) and whether they do so in a cumulative way over time; and (C) to develop a knowledge of the specific causal chains of mechanisms through which the residential context may affect cardiovascular health (we are especially interested in distinguishing between the different mediating pathways, such as modification of health-related behaviour and psychosocial processes). Our work may have important public health repercussions, in allowing policymakers to identify places with a higher risk of disease and tailor interventions adapted to the specific pathogenic mechanisms through which the context affects cardiovascular health.

One of the most prominent features of the cellular stress response, is the phosphorylation of the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2-a). This phosphorylation impacts many functional compartments of the cell, in a response known as the integrated stress response (ISR). The research consortium assembled for this project has a great expertise in the stress pathways involved in eIF2-a phosphorylation. Each laboratory has demonstrated individually the importance of several branches of the ISR for the control of eIF2-a phosphorylation during studies as diverse as the impact of anticancer agents on the immunogenicity of tumors, the production of cytokines during the detection of pathogens by innate immune cells (Clavarino et al. in revision) or the ability of mammalian cells to respond to amino acids starvation. Although these results were obtained independently, they all intersect and raise important questions on the role of the ISR and the regulation of eIF2-a phosphorylation in the initiation of the immune response, as well as tumorogenesis. As a result, our collective aim is to define the molecular characteristics and specificities of the different ISR(s) induced in response to various chemotherapeutic agents,microbial stimuli or physiological disorders. In particular, we need to establish how autophagy, translation and the ISR are co-regulated in response to stress and how these important biochemical functions can be manipulated, through the identification of novel molecular targets. We will further explore the importance of the ISR both during inflammation and tumor development/treatment by studying the negative feed-back mechanism preventing cell death during stress. The dephosphorylation of eIF2-a though the induced expression of Ppp1r15a (GADD34), which forms a functional complex with protein phosphatase 1 (PP1) and thereby restore protein synthesis, will be at the center of this study. In particular the use of GADD34 specific inhibitors that competitively disrupt the interaction between PP1 and GADD34 will be tested in different experimental conditions and mouse disease models. Each of the teams of the consortium has developed a range of technical expertise and experimental tools, which will be of great importance for the study of the biochemical pathways structured around eIF2-a phosphorylation in vitro and in vivo.