Successful new venturing process implemented by the founding entrepreneur: A case of Finnish sawmill industry

The fundamental purpose of this research is to emphasise a founding entrepreneur’s own role in the construction of a successful business story, with the focus being on the analysis of the entrepreneur’s activities. The theoretical section sheds light on the heterogeneous nature of existing performance research and, thereby, opens the way for the behavioural approach research of entrepreneurs in the field of new venture performance research. This research can be seen to be in line with the latest trends in entrepreneurship research, which question the applicability of different organisational theories in entrepreneurship research. For this reason, the founding entrepreneur has been chosen, instead of the company, to be the unit of analysis in this research in order to lighten the link in question while developing and refining new knowledge in the field of entrepreneurship. The empirical section of this research focuses on the entrepreneur’s own actions or behaviours that can be seen to be associated with the company’s success. Although some of these actions may resemble the strategic actions of a company as defined in strategic management literature, these actions taken by the entrepreneur themselves must be distinguished from the different organisational actions. Usually, an entrepreneur makes decisions rather independently, mainly on basis of their own intuition and prevailing market conditions, whereas organisational actions are very systematic, and each decision involves many different people. For this reason, an entrepreneur’s actions must be distinguished from organisational actions. In additional to different action paths, the empirical data collected for this research also offers almost unambiguous proof that the actions taken by an entrepreneur at the different stages of a company’s development do play a crucial role in the success of the companies studied in this research. In this way, it is possible to identify a significant link between the behavioural approach research of entrepreneurs and new venture performance research. Due to a lack of behavioural research into founding entrepreneurs, this research has utilised a qualitative (hermeneutic) research approach. The researcher strove to establish a particularly close connection with the entrepreneurs that were studied here and, thus, understand the actions taken at the different stages of their companies’ development as well as the motives and fundamental purposes of these actions. It would not have been possible to manage such profound data that focuses on causalities by using quantitative methods. In addition to interviews, this research used corporate histories of the companies for collecting some of the research data. These corporate histories can be considered excellent tools for the researcher to obtain a preliminary understanding and can, thereby, be seen to have laid the ground for more in-depth and diverse analyses.

Julkisten kansallisten palveluhankintojen tarjouspyyntöjen laatimisen ongelmakohdat

Viime vuosien aikana palveluhankintojen suhteellinen osuus kaikista toteutetuista julkisista hankinnoista on kasvanut Suomessa huomattavasti. Samalla markkinaoikeudessa on käsitelty vuosittain suuri määrä erilaisiin julkisiin hankinta-asioihin liittyviä valituksia. Merkittävä valitusten määrä on seurausta siitä, että julkisissa hankintaprosesseissa tehdään paljon virheitä. Tarjouspyynnön laatiminen on tärkeä hankintaprosessin vaihe, johon hankintayksiköissä tulisi kalliit markkinaoikeuskäsittelyt välttääkseen riittävästi panostaa. Tämän tutkielman tavoitteena oli selvittää, mitkä asiat palveluhankintojen tarjouspyyntöjen laatimisessa tuottavat hankintayksiköille ongelmia. Lisäksi tarkoituksena oli pohtia sekä itse palvelun hankkijaan että julkisten hankintojen lainsäädäntöön liittyviä tekijöitä, joista ongelmat palveluhankintojen tarjouspyyntöjen laatimisessa mahdollisesti johtuvat. Tutkimuksessa tutkimuskohteena olivat 24 markkinaoikeuden vuosina 2012–2014 antamaa hankinta-asioiden ratkaisua, ja tutkimus toteutettiin kvalitatiivisena tutkimuksena tutkimusaineistoa kategorisoimalla ja yhdenmukaistamalla. Tutkielmassa havaittiin, että merkittävin kompastuskivi kansallisten palveluhankintojen tarjouspyyntöjen laatimisessa on tarjouksen vertailuperusteiden asettaminen. Erityisesti laadun vertailuperusteiden tulkinnanvarainen ja epäselvä esittäminen oli yleistä, ja lisäksi merkittävä määrä virheitä tehtiin sekoittamalla tarjoajan soveltuvuusvaatimukset vertailuperusteisiin. Joitakin virheitä tehtiin myös vertailuperusteiden tärkeysjärjestyksen ja suhteellisen painotuksen asettamisessa sekä hankinnan kohteen määrittelyssä. Tutkimustulosten perusteella pääteltiin, että kansallisten palveluhankintojen tarjouspyyntöjen laatimisen ongelmissa on suurimmassa osin kyse hankintayksikön vähäisistä resursseista ja siten heikosta hankintojen suunnittelusta sekä hankintayksiköiden ammattitaidon ja kokemuksen puutteista. Lisäksi joitakin esiintyneitä virheitä voidaan ainakin jossain määrin perustella hankintalainsäädännön monimutkaisuudella ja tulkinnanvaraisuudella.

Tuotehallinnan kehittäminen ICT-palveluyrityksessä

Tuotehallinta on yrityksissä keskeinen arvoa tuottava toiminto, joka hallinnoi ja johtaa tuotteiden elinkaarta aina ideavaiheesta tuotteiden lopettamiseen saakka. Tuotteiden hyvän kilpailukyvyn kautta yritys saa kilpailuetua markkinassa. Tutkimuksen kohteena oleva case-yritys haluaa kehittää tuotehallinnan toimintaa, jotta se kykenee toimimaan aiempaa tehokkaammin ja menestymään paremmin tiukasti kilpailluilla markkinoilla. Diplomityön päätavoitteena oli löytää keinoja kohdeyrityksen yritysliiketoiminnan tuotehallinnan kehittämiseksi. Tutkimus toteutettiin laadullisena tapaustutkimuksena. Tutkimuksessa käytiin läpi aihealueen tuoretta tutkimustietoa sekä aiempaa teoriaa. Työssä tutkittiin kohdeyrityksen tuotehallinnan nykytilannetta ja kehittämismahdollisuuksia. Saatujen tutkimustulosten pohjalta ja tunnistettua teoriaa hyödyntäen johdettiin konkreettisia kehitystoimenpiteitä. Työ tuotti kriittisen näkökulman tuotehallinnan nykytilanteeseen sekä esityksen tärkeimmiksi tunnistetuista kehittämistoimenpiteistä. Tutkimuksen keskeisimpänä tuloksena toimii johtopäätös tarpeesta rakentaa aiempaa vahvempi tuotehallinta. Tämän aikaansaamiseksi tulee tehdä joukko kehittämistoimenpiteitä, jotka jaettiin lyhyen ja pitkän aikavälin toimenpiteisiin. Kehitystoimenpiteiden toteut-tamiseksi esitetiin muodostettavan oma hallittu kehitysohjelma.

Exploring knowledge worker motivation in autonomous and interdependent problem solving tasks on virtual platforms

The objective of this study is to understand why virtual knowledge workers conduct autonomous tasks and interdependent problem solving tasks on virtual platforms. The study is qualitative case study including three case organizations that tap the knowledge of expert networks, and utilize virtual platforms in the work processes. Research data includes 15 interviews, that is, five experts from each case company. According to the findings there are some specific characteristics in motivation to work on tasks on online platforms. Autonomy, self-improvement, meaningful tasks, knowledge sharing, time management, variety of contacts, and variety of tasks, and projects motivate virtual knowledge workers. Factors that may enhance individuals’ engagement to work on tasks are trust, security of continuous task flow and income, feedback, meaningful tasks and tasks that contribute to self-improvement, flexibility and effectiveness in time management, and virtual tools that support social interaction. The results also indicate that there are some differences in individuals’ motivation based on the tasks’ nature. That is, knowledge sharing and variety of contacts motivated experts who worked on interdependent problem solving tasks. Then again, autonomy and variety of tasks motivated experts who worked on autonomous tasks.

THE ADAPTATION PROCESS AND CHALLENGES OF EDUCATION EXPORT

The purpose of this study is to investigate the challenges of the adaptation process of education export. The research is conducted as a single case study that concentrates on three education export projects. The case company in the research is Team Academy. The study goes through the different forms of education export, the adaptation of education export and the challenges of the education export –process by means of theory and empirical data. The research is carried out as a qualitative research and the method used is a qualitative content analysis. More specifically the research is an abductive content analysis. The research data is collected in four in-depth interviews from Team academy representatives who have been strongly involved in certain education export –project of Team Academy. The research confirms the theory in the challenge of hierarchy, funding and registration issues, and refutes it in the challenge of competition, legislation, different governmental attitudes and knowledge in productization. The main challenges of the adaptation process are related to funding, differences in values, sudden changes, the complex nature of the learning model, concept of time, teamwork as method and accreditation. It is highlighted that in the future operations, anticipating problems that arise from for example cultural differences and differences in values, communication, managing the money flows and the company form is recommended. Future research could continue with investigating the suitable company form for education exports of this kind, and how to stand out and communicate when operating under another institution. It is considered a potential risk that a brand encloses the brand that operates under it.

Tehohoitopotilaan siirtotiedote hoitotyön päätöksenteon tukena - retrospektiivinen asiakirja-analyysi vuosilta 2001-2013

Tuija Lehtikunnas: Intensive care patient handover document in support of decision-making in nursing work - Retrospective document analysis for the period 2001–2013 University of Turku, Faculty of Medicine, Nursing Science Annales Universitatis Turkuensis Turku 2016 ABSTRACT The continuity of care and flow of information must be ensured when transferring the responsibility of care, whether this is done within an organisation or from one organisation to another. The purpose of this study was to describe and compare the nursing handover documents of long-term intensive care patients and changes to these documents during the years 2001–2013. Research data comprehended long-term intensive care patient handover documents (N = 250). Data was gathered from one university hospital intensive care unit and subjected to a content analysis of technical implementation, structure and content at five different time points. In addition to this, the nursing handover documents were analysed from a nursing decision-making standpoint. Sub-data (n = 5 x 50) from the years 2001, 2002, 2004, 2006 and 2013 was gathered. The first sub-data was manual, written on paper with a pen. The rest of the sub-data obtained was entered in a dedicated intensive care information system. The study developed an intensive care patient nursing handover document analysis framework, which was used to deductively analyse the research data. The results indicated that the transitioning to electronic records reinforced structure and identification improving the reusability of data was increased. Although intensive care nursing was recorded on nursing handover documents more comprehensively in more recent sub-data, it was done selectively with regard to overall patient care, e.g. there are no entries concerning the psychological support and counselling of patients or family members. Nursing handover documents do not contain a systematic description of the patient's communication and functional capacity at the moment of transfer. The patient's condition at the moment of transfer is not clearly indicated on the handover documents. Plans for follow-up treatment are not recorded at all. Nursing decision-making is difficult to find on the nursing handover documents used as research data. The study developed a handover document model for intensive care nursing that supports nursing decision-making and the continuity of care. Developmental recommendations focus on the management of co-operation within organisations for ensuring the continuity of care and enhancing each area of nursing in recording nursing handover documents by planning nursing for the patient, taking follow-up treatment resources into consideration. Keywords: Intensive care nursing, nursing decision-making, nursing records, information flow, nursing handover document, continuity of care

Offshoring and outsourcing under demand uncertainty -a supply chain management analysis

Outsourcing and offshoring or any combinations of these have not just become a popular phenomenon, but are viewed as one of the most important management strategies due to the new possibilities from globalization. They have been seen as a possibility to save costs and improve customer service. Executing offshoring and offshore outsourcing successfully can be more complex than initially expected. Potential cost savings resulting from of offshoring and offshore outsourcing are often based on lower manufacturing costs. However, these benefits might be conflicted by a more complex supply chain with service level challenges that can respectively increase costs. Therefore analyzing the total cost effects of offshoring and outsourcing is necessary. The aim of this Master´s Thesis was to to construct a total cost model using academic literature to calculate the total costs and analyze the reasonability of offshoring and offshore outsourcing production of a case company compared to insourcing production. The research data was mainly quantitative and collected mainly from the case company past sales and production records. In addition management level interviews from the case company were conducted. The information from these interviews was used for the qualification of the necessary quantitative data and adding supportive information that could not be gathered from the quantitative data. Both data collection and analysis were guided by a theoretical frame of reference that was based on academic literature concerning offshoring and outsourcing, statistical calculation of demand and total costs. The results confirm the theories that offshoring and offshore outsourcing would reduce total costs as both offshoring and offshore outsourcing options result in lower total annual costs than insourcing mainly due to lower manufacturing costs. However, increased demand uncertainty would make the alternative of offshore outsourcing more risky and difficult to manage. Therefore when assessing the overall impact of the alternatives, offshoring is the most preferable option. As the main cost savings in offshore outsourcing came from lower manufacturing costs, more specifically labour costs, the logistics costs in this case company did not have an essential effect in total costs. The management should therefore pay attention initially to manufacturing costs and then logistics costs when choosing the best production sourcing option for the company.

Managing Finnish-Russian Business Relationships and Networks During Conflicts

This thesis examines management of business relationships during conflicts. The context of this study is the international political conflict which started in 2013 and is still affecting international trade relations in 2016. More specifically, this study researches the effects of the conflict in Finnish-Russian trade. The research aim is to identify the implications of a political conflict in the Finnish-Russian business relationships and networks. Furthermore, the study will explore how does a company adapt or overcome the challenges and barriers posed by the international business environment. This research combines relevant theories in management of business relationships and networks in order to review the research data through a critical research frame. The theoretical frameworks are different structures of business relationship development processes, various stages of interaction, and characteristics and functions of business relationships. Moreover, this study will examine the effect of interdependency, commitment and trust in trade relations. Also, what are the important exchange processes and how do these processes affect business relationship and overall performance of joint business operations. Qualitative single case study method was used in this research. Case company was a Finnish multinational company. To understand the changes, the data was collected and analysed through process research approach by pattern-matching and drawing temporal bracketing over two different periods of time, first period in years 2011-2013 and second period in years 2014-2016. Empirical data was collected through a semi-structured interview and additional data was collected from internal and external secondary data sources. The findings of the study confirmed the relationship between trade and conflict. However, the effects are not significant for a company in grocery retail industry which has had earlier experience in Russia and has managed its business relationships and operations effectively. Macroeconomic factors affect companies operating in foreign dynamic markets and in order to sustain changes and to adapt, companies should invest in their business relationships. Trust-based relationships and a higher level of commitment allow companies to have more efficient and beneficial outcomes before and during uncertainty. Furthermore, well-maintained and coordinated business relationships provide the ability to adapt and overcome challenges during uncertainty. Such relationships have information, financial and social exchange processes which allow the partnering firms to have successful business relationship management in dynamic market environments.

Internal communication during an organizational change: An ethnographic case study

This study discusses the importance of internal communication during organizational change of a case study company X. The purpose of this study is to find out how to use internal communication effectively during organizational change. This study is an ethnographic cade study where a unique case of an organizational change was chosen as the research object. The theoretical background of this study consists of literature relating to the concepts of communication, organizational communication, organizational change, change management and communication of change. The empirical research conducted for this study is based on an ethnographic research method where data was collected through participant observation, informal interviews and field records in the form of a research diary. The research data was collected between September and December 2015. During this period the researcher was working within the case study organization while observing the internal communication during the organizational change process. Triangulation was used to analyze the research data in order to build a united and theoretical picture of the topic. The study finds that without clear internal communication strategy the effectiveness of communication is ought to be poor, which may lead to resistance of change, lack of trust and lower level of overall job satisfaction. Moreover the study findings highlight the importance of managerial presence during an organizational change process and consistency in using formal and informal communication and utilizing multiple communication channels. Based on the findings of this research the study suggests that during an organizational change process a clear internal communication strategy should be carefully planned and executed. The goals of internal communication should be clearly stated and communicated to the company’s employees. The findings of this study enhance importance of managers promoting sense of belonging, developing awareness of the overall change process and contributing to the manager employee relationships and trust. In addition this study points out the key factors that should be included in the internal change communication strategy which are how to ensure that the communications, both vertical and horizontal, are constant. Future research is however necessary in order to gain a more comprehensive view of the research and wider perspective of the case study. Nevertheless, this study deepens the understanding of how to use internal communication effectively during organizational change.

Invisible disability, visible people: a closer look at the experiences of teachers with learning disabilities /

Throughout their schooling experiences, students with learning disabilities (LD) face numerous academic and socioemotional challenges. Some of these individuals rise above these obstacles to obtain a postsecondary education and become professionals. Recently, there have been a number of individuals with learning disabilities who have chosen a career in teaching. There is a lack of research that documents the experiences of teachers with learning disabilities. The purpose of this qualitative study is to gain an understanding of the challenges that the teachers with learning disabilities strive to overcome and the supports that they receive ^^^ch facilitate their inception into teaching. Four teachers with learning disabilities were the participants in this collective case study research. Data were collected through semistructured interviews. These data were coded, collapsed into themes, and the results were presented in a narrative form. The resultant 9 themes are: (a) Perspectives on School Experiences, (b) Identification and Effective Accommodations, (c) Isolation, Frustration, and Support, (d) Awareness of Learning Disability at Age 18, (e) Disclosure of Learning Disability, (f) Negative Impact of the Learning Disability Label, (g) Desire, Drive, and Obstacles, (h) Empathy, Compassion, and Self-Concept, and (i) Critical Views of Colleagues. The themes reflect the common experiences among participants. The discussion brings forth new information that is not found in other research. The impHcations of this research will interest teacher federations, parents of students with LD, teachers, and educational researchers.

Business leadership in the classroom

This action research assesses a framework that assists business educators in promoting leadership within a classroom. It is designed to better prepare students to assume leadership and fill the "leadership gap" in business. Two classes of 2nd-year community college business students participated in running and managing their own business community as teams of sales professionals by developing and practicing their own individual leadership for 28 weeks during their sales courses. The intent was to assess the development of leadership resulting from the implementation of the "Business Leadership in the Classroom" framework. This framework balances leadership principles to simulate a business environment with the practical elements of a learning community under the facilitation of an experienced business educator. The action research approach was used to assess and adjust approaches to business leadership on a continuous basis throughout the research. Data were collected from 61 students based on journals, surveys, peer group reviews, and my (facilitator) reflective journal.The findings reveal that both individual and collective business leadership views and practical skills developed over time. A business leadership mind-set evolved that ranged from a general awareness of the importance of leadership, to a conscious and deliberate use of individual leadership. Areas important in building a progression of leadership included: leadership teams, membership roles, weekly leadership teams, peer feedback, and activity-based learning. Emerging themes included leadership, leadership style, teamwork, as well as influence and motivation. The research framework was effective in supporting the development of business leadership but required some adjustments. These included increased structure and feedback mechanisms. Interpretation of the findings demonstrates the importance of real-world practical education in the classroom. Results show how focusing on a single mind-set such as business leadership, can result in enormous individual growth and development. When business students are encouraged to act as real businesspeople, managing their own learning, the results are effective in preparing them for the business world. All participants expressed their leadership in different ways based on personality and individual strengths. There was an overwhelming and, in some cases, passionate interest in leadership. The use of action research with a range of data collection methods provides a way to measure and track individual student learning and to generate adjustments to the research framework design and learning approaches. The findings generate implications and recommendations to continue this research further. Key recommendations center around how to ensure leadership development is sustained, including improved approaches to heighten the real-world feel of the classroom. Specifically, the use of leadership goals and action plans for each individual participant and an active use of outside business resource people as contacts for participants is recommended.

Children's Bullying Experiences and Self-Worth Perceptions in a Private School

This study explored children's bullying experiences (as bully, victim, and bystander) and their self-worth perceptions in a private school in Ontario, Canada. Forty students from 12 different countries participated in a mixed methodology (both quantitative and qualitative) research design using a self-report questionnaire. Students reported involvement in bullying as a bully, victim, and bystander. The overall results reveal a pattern across the three roles where the degree of bullying observed as a bystander is the highest (57%) followed by the experiences as a victim (29%) and that performed as bully (21%). The bystanders reported direct bullying being witnessed, bullies reported indirect bullying interventions as being used, and victims of bullying reported indirect bullying being the most common type of bullying they experienced. Decreased feeling of self-worth is reported in the qualitative research data in regards to bullying. Boarding students reported issues regarding personal safety, need for social relationships, self-worth, and unacceptability of bullying. Implications for practice for the private school are discussed, focusing on the outcome of this study.

L’asphyxie en médecine légale : une étude rétrospective de six ans sur les suffocations non-chimiques au Québec

La suffocation est une forme d’asphyxie dans laquelle l’oxygène ne peut atteindre le sang. Il existe divers types de suffocation dont la suffocation par confinement/ environnementale, les étouffements externe et interne, et les asphyxies traumatique/ positionnelle. La littérature scientifique sur la suffocation est relativement pauvre, étant principalement constituée de revues de cas et de quelques séries de cas limités à un contexte particulier de suffocation. Dans le contexte actuel d’une médecine basée sur les preuves, les ouvrages de médecine légale n’ont guère d’études pour appuyer leurs enseignements, tirés essentiellement de l’expérience personnelle de générations de médecins légistes. Le présent projet vise à palier ce manque de données sur la suffocation, un type de décès pourtant important en pratique médico-légale. Il s’agit d’une étude rétrospective de six ans portant sur tous les cas de suffocation non-chimique ayant été autopsiés au Laboratoire de sciences judiciaires et de médecine légale. À notre connaissance, cette étude est la première à établir le portrait systématique des morts par suffocation non-chimique en milieu médico-légal. Elle permet, entre autres, de confirmer les modes de décès usuels par catégorie de suffocation, le type de victime et les contextes courants. Généralement, les résultats concordent avec la littérature, appuyant ainsi le savoir commun des pathologistes sur la suffocation non-chimique. Toutefois, certaines dissimilitudes ont été notées quant aux modes de décès lors de l’étouffement externe. Par ailleurs, les questions reliées à la classification des asphyxies et aux définitions souvent contradictoires sont discutées. En un effort de normalisation, ce projet souligne les divergences retrouvées dans les classifications usuelles et tente d’en dégager les définitions courantes afin de proposer un modèle de classification unifié.

A Categorical Framework for the Specification and the Verification of Aspect Oriented Systems

Un objectif principal du génie logiciel est de pouvoir produire des logiciels complexes, de grande taille et fiables en un temps raisonnable. La technologie orientée objet (OO) a fourni de bons concepts et des techniques de modélisation et de programmation qui ont permis de développer des applications complexes tant dans le monde académique que dans le monde industriel. Cette expérience a cependant permis de découvrir les faiblesses du paradigme objet (par exemples, la dispersion de code et le problème de traçabilité). La programmation orientée aspect (OA) apporte une solution simple aux limitations de la programmation OO, telle que le problème des préoccupations transversales. Ces préoccupations transversales se traduisent par la dispersion du même code dans plusieurs modules du système ou l’emmêlement de plusieurs morceaux de code dans un même module. Cette nouvelle méthode de programmer permet d’implémenter chaque problématique indépendamment des autres, puis de les assembler selon des règles bien définies. La programmation OA promet donc une meilleure productivité, une meilleure réutilisation du code et une meilleure adaptation du code aux changements. Très vite, cette nouvelle façon de faire s’est vue s’étendre sur tout le processus de développement de logiciel en ayant pour but de préserver la modularité et la traçabilité, qui sont deux propriétés importantes des logiciels de bonne qualité. Cependant, la technologie OA présente de nombreux défis. Le raisonnement, la spécification, et la vérification des programmes OA présentent des difficultés d’autant plus que ces programmes évoluent dans le temps. Par conséquent, le raisonnement modulaire de ces programmes est requis sinon ils nécessiteraient d’être réexaminés au complet chaque fois qu’un composant est changé ou ajouté. Il est cependant bien connu dans la littérature que le raisonnement modulaire sur les programmes OA est difficile vu que les aspects appliqués changent souvent le comportement de leurs composantes de base [47]. Ces mêmes difficultés sont présentes au niveau des phases de spécification et de vérification du processus de développement des logiciels. Au meilleur de nos connaissances, la spécification modulaire et la vérification modulaire sont faiblement couvertes et constituent un champ de recherche très intéressant. De même, les interactions entre aspects est un sérieux problème dans la communauté des aspects. Pour faire face à ces problèmes, nous avons choisi d’utiliser la théorie des catégories et les techniques des spécifications algébriques. Pour apporter une solution aux problèmes ci-dessus cités, nous avons utilisé les travaux de Wiels [110] et d’autres contributions telles que celles décrites dans le livre [25]. Nous supposons que le système en développement est déjà décomposé en aspects et classes. La première contribution de notre thèse est l’extension des techniques des spécifications algébriques à la notion d’aspect. Deuxièmement, nous avons défini une logique, LA , qui est utilisée dans le corps des spécifications pour décrire le comportement de ces composantes. La troisième contribution consiste en la définition de l’opérateur de tissage qui correspond à la relation d’interconnexion entre les modules d’aspect et les modules de classe. La quatrième contribution concerne le développement d’un mécanisme de prévention qui permet de prévenir les interactions indésirables dans les systèmes orientés aspect.

Étude de la Structure-Fonction du Prosegment et du domaine CHRD de la PCSK9 humaine

L’excès des particules de LDL dans le sang constitue un facteur de risque majeur dans le développement des maladies cardiovasculaires. Dans ce contexte, nous étudions la protéine PCSK9 qui favorise directement ce facteur de risque. Cette protéine est sécrétée en majorité au niveau du foie par les hépatocytes et possède la capacité de reconnaître et de lier le récepteur LDLR. Le rôle premier de ce dernier est d’éliminer les particules de LDL circulant dans le plasma. Ainsi, lorsque la PCSK9 forme un complexe avec le LDLR et l’amène à la dégradation, la conséquence directe de la diminution des ces récepteurs est une accumulation malsaine des particules LDL dans le plasma. L’importante implication de la PCSK9 dans le métabolisme des lipides nous a menés vers des recherches de caractérisation de cette protéine ainsi que dans l’étude de son mode d’action. La PCSK9 est composée de trois domaines et notre intérêt s’est porté sur l’étude structure-fonction des deux domaines dont la fonction était inconnue, soit le domaine en N-terminal : le prodomaine et de son domaine en C-terminal : CHRD. Le premier article présenté dans cette thèse révèle l’importance d’une région acide (acide aminés 33-58) régulatrice de l’activité de la PCSK9 localisée en N-terminal du prodomaine ainsi que l’effet du pH acide, équivalent à celui des endosomes tardifs, qui accroît la capacité de la PCSK9 à induire la dégradation du LDLR. Le deuxième article dissèque davantage la structure de la PCSK9 et met en lumière la différence des prérequis structurels de la région ‘’Hinge’’ ainsi que du module M2, composant du domaine CHRD, dans la voie intracellulaire et la voie extracellulaire d’activité de la PCSK9. La mutation R434W localisée dans la région ‘’Hinge’’ résulte dans une inhibition totale de l’activité intracellulaire de la PCSK9 tandis que son activité extracellulaire est réduite à ~70%. Contrairement, la perte du module M2 du domaine CHRD est bien tolérée par la PCSK9 lors de son activité intracellulaire mais totalement inhibitrice pour son activité extracellulaire. Le troisième article se distingue en présentant une nouvelle stratégie d’inhibition de l’activité de la PCSK9 en utilisant une chimère composée de la fraction Fc de l’immunoglobuline IgG1 humaine couplée avec le prodomaine de la PCSK9. La protéine fusion Fcpro lie directement la PCSK9, crée un encombrement structurel qui résulte dans une régulation négative l’activité de la PCSK9. En résumé, nous présentons dans cette thèse, trois manuscrits qui apportent une contribution à la connaissance des composantes structurelles de la PCSK9 et leur implication dans le rôle de la protéine en tant que régulateur négatif du LDLR.