Depuis son accession à l’indépendance, le Burkina Faso est à la recherche d’une politique publique de développement qui lui permette de sortir de son état de « sous-développement ». La politique budgétaire a, de ce fait, été instituée en catalyseur d’un développement économique et social durable. Mais les errements budgétaires des Gouvernements qui se sont succédé ont plutôt entraîné une triple crise : une crise de la dette, une crise des déficits publics et une crise économique. A compter des années 1990, le FMI et la Banque Mondiale sont intervenus, aux côtés des autorités burkinabé, dans le cadre d’une double assistance technique et financière afin de réformer, structurellement, la politique budgétaire. Cette intervention va s’installer durablement dans la politique interne burkinabé. En deux décennies, la politique des finances sera orientée au gré de la doctrine budgétaire et des priorités définies par le FMI et la Banque Mondiale : les programmes d’ajustement structurel, puis la politique de lutte contre la pauvreté vont tenter de réaliser les objectifs de croissance économique, puis de croissance économique et sociale, grâce à une réforme de la politique de dépenses budgétaires et de la politique de ressources budgétaires. Seulement, quelque soit l’objectif pris en considération, les résultats atteints restent bien éloignés des résultats escomptés en termes de restructuration de la dette, des dépenses et des ressources budgétaires. Cette dynamique de réformes permet néanmoins de s’interroger, au vu des expériences passées, sur le rôle à attribuer à l’Etat au Burkina Faso, à la politique budgétaire, au FMI et à la Banque Mondiale, aux institutions communautaires ouest-africaines dans le processus de développement que le Burkina Faso doit nécessairement relancer, afin que ces décennies de réformes ne soient pas considérées comme inutiles. / Since its independence, Burkina Faso is seeking public policy development that allows him to leave his state of "underdevelopment". Fiscal policy has, therefore, been established as a catalyst for sustainable economic and social development. But mistakes budget successive Governments have instead led to a triple crisis: a debt crisis, a crisis of deficits and an economic crisis. Beginning in the 1990s, the IMF and the World Bank intervened alongside Burkinabe authorities, within a double technical and financial assistance to reform structurally fiscal policy. This intervention will settle permanently in the internal politics of Burkina Faso. In two decades, finance policy will be geared to suit the budget doctrine and priorities defined by the IMF and the World Bank: the structural adjustment programs and the political fight against poverty will try to achieve the objectives of economic growth, and economic growth and social reform through policy and budgetary spending policy of budgetary resources. But whatever the goal under consideration, the results achieved are far removed from the expected results in terms of debt restructuring, expenditure and budgetary resources. This dynamic reforms can nevertheless wonder, in view of past experience, the appropriate role for the state in Burkina Faso, fiscal policy, the IMF and the World Bank, the Community institutions in West Africa the development process as Burkina Faso must necessarily raise, so that decades of reforms are not considered necessary.

Ces travaux de thèse s'articulent autour de deux projets : les études structure-fonction de l'aminopeptidase A, d'une part, et celles du récepteur de l'apéline, d'autre part. I/ L'aminopeptidase A (APA, EC 3.4.11.7) est une aminopeptidase monozinc membranaire qui, dans le cerveau, produit l'angiotensine (Ang) III à partir de l'Ang II. L'Ang III est l'un des principaux peptides effecteurs du système rénine-angiotensine cérébral qui exerce un effet stimulateur tonique sur le contrôle central de la pression artérielle chez le rat hypertendu. Ainsi le blocage de l'APA par un inhibiteur spécifique et sélectif, l'EC33 ou sa prodrogue, le RB150, normalise la pression artérielle dans deux modèles expérimentaux d'hypertension artérielle (HTA). L'APA constitue une cible thérapeutique potentielle pour le traitement de l'HTA qui justifie le développement de nouveaux inhibiteurs de cette enzyme plus puissants et plus sélectifs que l'EC33 et avec un profil pharmacodynamique et pharmacocinétique amélioré par rapport au RB150. Pour cela, nous avons construit un modèle tridimensionnel (3D) de l'APA sur la base de la structure cristallographique de l'APA humaine récemment publiée. Nous avons ensuite validé ce modèle par des études structure-fonction par modélisation moléculaire et mutagénèse dirigée en démontrant l'implication, d'un résidu du sous-site S1 dans la spécificité de substrat acide de l'APA et de deux résidus formant le sous-site S2' interagissant avec le résidu P2' acide d'inhibiteurs tripeptidiques précédemment développés dans le laboratoire.II/ L'apéline est le ligand naturel du récepteur orphelin humain APJ (ApélineR), un récepteur à sept domaines transmembranaires couplé aux protéines G. L'apéline et son récepteur sont impliqués dans le maintien de l'équilibre hydrique et des fonctions cardiovasculaires. L'ApélineR constitue une cible thérapeutique potentielle dans le traitement de l'insuffisance cardiaque et des rétentions hydriques. Etant donné que la demi-vie de l'apéline dans la circulation sanguine est de l'ordre de la minute, l'objectif est de développer des analogues de l'apéline métaboliquement stables. Pour développer de tels composés, nous avons entrepris de comprendre comment l'apéline se lie à son récepteur et comment elle l'active. Dans ce but, nous avons construit un modèle 3D de l'ApélineR basé sur la structure cristallographique du récepteur aux chimiokines, CXCR4. Nous avons validé ce modèle par des études structure-fonction par modélisation moléculaire et mutagénèse dirigée. Nous avons identifié à la surface du récepteur, les résidus acides des boucles extracellulaires qui interagissent avec les résidus basiques de l'apéline. Nous avons ensuite développé des analogues de l'apéline-17 (K17F) métaboliquement stables par deux stratégies différentes. Premièrement, nous avons substitué chacun des résidus de l'apéline par son énantiomère de la série D ou par un acide aminé synthétique. Deuxièmement, nous avons ajouté une chaîne fluoroalkyle à l'extrémité N-terminale de l'apéline. Ces deux stratégies ont permis d'obtenir plusieurs composés dont les plus actifs sont le P92 et le LIT01-196 qui conservent des propriétés pharmacologiques identiques à celles de K17F et qui présentent une demi-vie plasmatique largement supérieure à celle du peptide endogène. Ces deux analogues se sont révélés particulièrement actifs in vivo avec une capacité à diminuer la pression artérielle et à réduire la sécrétion de vasopressine dans le sang conduisant à une augmentation de la diurèse aqueuse. Les modèles 3D validés de l'APA et de l'ApélineR seront utilisés pour des campagnes de criblage in silico de chimiothèques virtuelles afin de découvrir de nouveaux inhibiteurs de l'APA et des agonistes de l'ApélineR qui pourraient conduire à terme à de nouveaux candidats-médicaments. Ces composés pourraient être utiles pour le traitement de l'HTA et de l'insuffisance cardiaque. / The doctoral work was divided in two parts, one on the structure-function studies of aminopeptidase A, and the second one, on those of the apelin receptor. I/ Aminopeptidase A (APA) is a membrane bound monozinc aminopeptidase which generates, in the brain, angiotensin (Ang) III from Ang II. Ang III is one of the main effector peptides of the brain renin-angiotensin system, which exerts a tonic stimulatory action on the control of blood pressure in hypertensive rats. Thus, the blockade of brain APA by a specific and selective inhibitor, EC33 or its prodrug, RB150, normalizes blood pressure in two animal models of arterial hypertension (HTA). APA constitutes a potential therapeutic target for the treatment of HTA that justifies the development of more potent and selective APA inhibitors than EC33, with enhanced pharmacodynamic and pharmacokinetic profiles when compared to RB150. With this aim, we built a three dimensional (3D) model of APA based on the recently published crystal structure of human APA. We validated this model by structure-function studies combining molecular modeling and site-directed mutagenesis demonstrating the crucial role of one residue in the S1 subsite responsible for substrate specificity of APA for N-terminal acidic amino-acid residues and two other residues constituting the S2' subsite of APA involved in the binding of the P2' acidic residue of tripeptidic inhibitors, previously developed in the laboratory. II/ Apelin is the endogenous ligand of the human orphan receptor named APJ (ApelinR), a G protein-coupled receptor. Apelin and ApelinR are involved in the control of body fluid homeostasis and cardiovascular functions. ApelinR constitutes a potential therapeutic target for the treatment of heart failure and water retentions. Given that apelin half-life in the blood circulation is in the minute range, we aimed to develop potent metabolically stable apelin analogs.. In this context, it is necessary to understand how apelin binds to ApelinR and how it is activated. To do so, we build a 3D model of ApelinR based on the crystal structure of the chemokine receptor, CXCR4. We validated this model by structure-function studies by molecular modeling and site-directed mutagenesis. We showed that apelin interacts with the receptor through interactions between the basic residues of the peptide and the acidic residues of the ApelinR, located in the extracellular loops. ,We then developed metabolically stable apelin-17 (K17F) analogs following two different strategies. First, we substituted each residue of K17F by its D-isomer or a synthetic amino-acid. Secondly, we added a fluoroalkyl chain at the N-terminal part of K17F. These two strategies allowed to significantly improve plasma half-life of the modified peptides for several hours without modifying their pharmacological properties as compared to K17F. Two apelin metabolically stable analogs, P92 and LIT01-196, were found to have significantly higher in vivo activity than K17F with a strong capacity to decrease blood pressure and to inhibit vasopressin release in the blood stream inducing an increased aqueous diuresis. These new validated 3D models will be now used to perform in silico screening of virtual chemical libraries to discover new APA inhibitors and ApelinR agonists that could ultimately lead to new drug candidates. These compounds could be useful for the treatment of HTA and heart failure.

This thesis addresses three relevant macroeconomic issues: (i) why<p>Central Banks behave so cautiously compared to optimal theoretical<p>benchmarks, (ii) do monetary variables add information about<p>future Euro Area inflation to a large amount of non monetary<p>variables and (iii) why national saving and investment are so<p>correlated in OECD countries in spite of the high degree of<p>integration of international financial markets.<p><p>The process of innovation in the elaboration of economic theory<p>and statistical analysis of the data witnessed in the last thirty<p>years has greatly enriched the toolbox available to<p>macroeconomists. Two aspects of such a process are particularly<p>noteworthy for addressing the issues in this thesis: the<p>development of macroeconomic dynamic stochastic general<p>equilibrium models (see Woodford, 1999b for an historical<p>perspective) and of techniques that enable to handle large data<p>sets in a parsimonious and flexible manner (see Reichlin, 2002 for<p>an historical perspective).<p><p>Dynamic stochastic general equilibrium models (DSGE) provide the<p>appropriate tools to evaluate the macroeconomic consequences of<p>policy changes. These models, by exploiting modern intertemporal<p>general equilibrium theory, aggregate the optimal responses of<p>individual as consumers and firms in order to identify the<p>aggregate shocks and their propagation mechanisms by the<p>restrictions imposed by optimizing individual behavior. Such a<p>modelling strategy, uncovering economic relationships invariant to<p>a change in policy regimes, provides a framework to analyze the<p>effects of economic policy that is robust to the Lucas'critique<p>(see Lucas, 1976). The early attempts of explaining business<p>cycles by starting from microeconomic behavior suggested that<p>economic policy should play no role since business cycles<p>reflected the efficient response of economic agents to exogenous<p>sources of fluctuations (see the seminal paper by Kydland and Prescott, 1982}<p>and, more recently, King and Rebelo, 1999). This view was challenged by<p>several empirical studies showing that the adjustment mechanisms<p>of variables at the heart of macroeconomic propagation mechanisms<p>like prices and wages are not well represented by efficient<p>responses of individual agents in frictionless economies (see, for<p>example, Kashyap, 1999; Cecchetti, 1986; Bils and Klenow, 2004 and Dhyne et al. 2004). Hence, macroeconomic models currently incorporate<p>some sources of nominal and real rigidities in the DSGE framework<p>and allow the study of the optimal policy reactions to inefficient<p>fluctuations stemming from frictions in macroeconomic propagation<p>mechanisms.<p><p>Against this background, the first chapter of this thesis sets up<p>a DSGE model in order to analyze optimal monetary policy in an<p>economy with sectorial heterogeneity in the frequency of price<p>adjustments. Price setters are divided in two groups: those<p>subject to Calvo type nominal rigidities and those able to change<p>their prices at each period. Sectorial heterogeneity in price<p>setting behavior is a relevant feature in real economies (see, for<p>example, Bils and Klenow, 2004 for the US and Dhyne, 2004 for the Euro<p>Area). Hence, neglecting it would lead to an understatement of the<p>heterogeneity in the transmission mechanisms of economy wide<p>shocks. In this framework, Aoki (2001) shows that a Central<p>Bank maximizing social welfare should stabilize only inflation in<p>the sector where prices are sticky (hereafter, core inflation).<p>Since complete stabilization is the only true objective of the<p>policymaker in Aoki (2001) and, hence, is not only desirable<p>but also implementable, the equilibrium real interest rate in the<p>economy is equal to the natural interest rate irrespective of the<p>degree of heterogeneity that is assumed. This would lead to<p>conclude that stabilizing core inflation rather than overall<p>inflation does not imply any observable difference in the<p>aggressiveness of the policy behavior. While maintaining the<p>assumption of sectorial heterogeneity in the frequency of price<p>adjustments, this chapter adds non negligible transaction<p>frictions to the model economy in Aoki (2001). As a<p>consequence, the social welfare maximizing monetary policymaker<p>faces a trade-off among the stabilization of core inflation,<p>economy wide output gap and the nominal interest rate. This<p>feature reflects the trade-offs between conflicting objectives<p>faced by actual policymakers. The chapter shows that the existence<p>of this trade-off makes the aggressiveness of the monetary policy<p>reaction dependent on the degree of sectorial heterogeneity in the<p>economy. In particular, in presence of sectorial heterogeneity in<p>price adjustments, Central Banks are much more likely to behave<p>less aggressively than in an economy where all firms face nominal<p>rigidities. Hence, the chapter concludes that the excessive<p>caution in the conduct of monetary policy shown by actual Central<p>Banks (see, for example, Rudebusch and Svennsson, 1999 and Sack, 2000) might not<p>represent a sub-optimal behavior but, on the contrary, might be<p>the optimal monetary policy response in presence of a relevant<p>sectorial dispersion in the frequency of price adjustments.<p><p>DSGE models are proving useful also in empirical applications and<p>recently efforts have been made to incorporate large amounts of<p>information in their framework (see Boivin and Giannoni, 2006). However, the<p>typical DSGE model still relies on a handful of variables. Partly,<p>this reflects the fact that, increasing the number of variables,<p>the specification of a plausible set of theoretical restrictions<p>identifying aggregate shocks and their propagation mechanisms<p>becomes cumbersome. On the other hand, several questions in<p>macroeconomics require the study of a large amount of variables.<p>Among others, two examples related to the second and third chapter<p>of this thesis can help to understand why. First, policymakers<p>analyze a large quantity of information to assess the current and<p>future stance of their economies and, because of model<p>uncertainty, do not rely on a single modelling framework.<p>Consequently, macroeconomic policy can be better understood if the<p>econometrician relies on large set of variables without imposing<p>too much a priori structure on the relationships governing their<p>evolution (see, for example, Giannone et al. 2004 and Bernanke et al. 2005).<p>Moreover, the process of integration of good and financial markets<p>implies that the source of aggregate shocks is increasingly global<p>requiring, in turn, the study of their propagation through cross<p>country links (see, among others, Forni and Reichlin, 2001 and Kose et al. 2003). A<p>priori, country specific behavior cannot be ruled out and many of<p>the homogeneity assumptions that are typically embodied in open<p>macroeconomic models for keeping them tractable are rejected by<p>the data. Summing up, in order to deal with such issues, we need<p>modelling frameworks able to treat a large amount of variables in<p>a flexible manner, i.e. without pre-committing on too many<p>a-priori restrictions more likely to be rejected by the data. The<p>large extent of comovement among wide cross sections of economic<p>variables suggests the existence of few common sources of<p>fluctuations (Forni et al. 2000 and Stock and Watson, 2002) around which<p>individual variables may display specific features: a shock to the<p>world price of oil, for example, hits oil exporters and importers<p>with different sign and intensity or global technological advances<p>can affect some countries before others (Giannone and Reichlin, 2004). Factor<p>models mainly rely on the identification assumption that the<p>dynamics of each variable can be decomposed into two orthogonal<p>components - common and idiosyncratic - and provide a parsimonious<p>tool allowing the analysis of the aggregate shocks and their<p>propagation mechanisms in a large cross section of variables. In<p>fact, while the idiosyncratic components are poorly<p>cross-sectionally correlated, driven by shocks specific of a<p>variable or a group of variables or measurement error, the common<p>components capture the bulk of cross-sectional correlation, and<p>are driven by few shocks that affect, through variable specific<p>factor loadings, all items in a panel of economic time series.<p>Focusing on the latter components allows useful insights on the<p>identity and propagation mechanisms of aggregate shocks underlying<p>a large amount of variables. The second and third chapter of this<p>thesis exploit this idea.<p><p>The second chapter deals with the issue whether monetary variables<p>help to forecast inflation in the Euro Area harmonized index of<p>consumer prices (HICP). Policymakers form their views on the<p>economic outlook by drawing on large amounts of potentially<p>relevant information. Indeed, the monetary policy strategy of the<p>European Central Bank acknowledges that many variables and models<p>can be informative about future Euro Area inflation. A peculiarity<p>of such strategy is that it assigns to monetary information the<p>role of providing insights for the medium - long term evolution of<p>prices while a wide range of alternative non monetary variables<p>and models are employed in order to form a view on the short term<p>and to cross-check the inference based on monetary information.<p>However, both the academic literature and the practice of the<p>leading Central Banks other than the ECB do not assign such a<p>special role to monetary variables (see Gali et al. 2004 and<p>references therein). Hence, the debate whether money really<p>provides relevant information for the inflation outlook in the<p>Euro Area is still open. Specifically, this chapter addresses the<p>issue whether money provides useful information about future<p>inflation beyond what contained in a large amount of non monetary<p>variables. It shows that a few aggregates of the data explain a<p>large amount of the fluctuations in a large cross section of Euro<p>Area variables. This allows to postulate a factor structure for<p>the large panel of variables at hand and to aggregate it in few<p>synthetic indexes that still retain the salient features of the<p>large cross section. The database is split in two big blocks of<p>variables: non monetary (baseline) and monetary variables. Results<p>show that baseline variables provide a satisfactory predictive<p>performance improving on the best univariate benchmarks in the<p>period 1997 - 2005 at all horizons between 6 and 36 months.<p>Remarkably, monetary variables provide a sensible improvement on<p>the performance of baseline variables at horizons above two years.<p>However, the analysis of the evolution of the forecast errors<p>reveals that most of the gains obtained relative to univariate<p>benchmarks of non forecastability with baseline and monetary<p>variables are realized in the first part of the prediction sample<p>up to the end of 2002, which casts doubts on the current<p>forecastability of inflation in the Euro Area.<p><p>The third chapter is based on a joint work with Domenico Giannone<p>and gives empirical foundation to the general equilibrium<p>explanation of the Feldstein - Horioka puzzle. Feldstein and Horioka (1980) found<p>that domestic saving and investment in OECD countries strongly<p>comove, contrary to the idea that high capital mobility should<p>allow countries to seek the highest returns in global financial<p>markets and, hence, imply a correlation among national saving and<p>investment closer to zero than one. Moreover, capital mobility has<p>strongly increased since the publication of Feldstein - Horioka's<p>seminal paper while the association between saving and investment<p>does not seem to comparably decrease. Through general equilibrium<p>mechanisms, the presence of global shocks might rationalize the<p>correlation between saving and investment. In fact, global shocks,<p>affecting all countries, tend to create imbalance on global<p>capital markets causing offsetting movements in the global<p>interest rate and can generate the observed correlation across<p>national saving and investment rates. However, previous empirical<p>studies (see Ventura, 2003) that have controlled for the effects<p>of global shocks in the context of saving-investment regressions<p>failed to give empirical foundation to this explanation. We show<p>that previous studies have neglected the fact that global shocks<p>may propagate heterogeneously across countries, failing to<p>properly isolate components of saving and investment that are<p>affected by non pervasive shocks. We propose a novel factor<p>augmented panel regression methodology that allows to isolate<p>idiosyncratic sources of fluctuations under the assumption of<p>heterogenous transmission mechanisms of global shocks. Remarkably,<p>by applying our methodology, the association between domestic<p>saving and investment decreases considerably over time,<p>consistently with the observed increase in international capital<p>mobility. In particular, in the last 25 years the correlation<p>between saving and investment disappears.<p> / Doctorat en sciences économiques, Orientation économie / info:eu-repo/semantics/nonPublished

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