Preface Tbenty-five Years of the Gaubius Institute The Gaubius Institute was established by the University of Leiden in 1965 to provide a center fbr multidisciplinary rrsearch. The aim was to develop a research p u p that could apply its knowledge in physical chemistry to medical research. Since its early days, the Gaubius Institute was a6Iiated with both the University of Leiden and the Organization fbr Applied Scientific Research (TNO).The majority of the Institute's staffwere permanently attached to TNO's Health Research Division. In 1973, however, the Institute became fully integrated with TNO,but retained its premises in the old city of Leiden. Many guests from other countries have visited the Gaubius Institute and have seen the quaint, picturesque but practical ficilities. In April 1991 the Institute became a part of the new TNO Institute of Ageing and Vascular Research and was re-housed in a new building, known as the Gaubius Laboratory, close to the University's Hospital and Science Faculties. At the time of its establishment, the principal role of the Institute was to investipte chemical aspects of arteriosclerosis and thrombosis. New methods and analytical techniques were developed-notably physicochemical separation and detection methods fbr the study of the constituents of the diseased arterial wall. For those studies substantial support h m the National Institutes of Health was received. In the early seventies, Biochemistry, Protein Chemistry, and Immunology were added as rcscarch tools. These were fbllowed by Cell Culture (endothelial- and liver cells) and Hybridoma Technology. Later Molecular Biology and Molecular Genetics were added. Animal experimentation is canied out to a limited extent. Both nscarch on i h d a mental mechanisms and clinical research are essential fbr the solution of medical problems. Therefbre, the Institute closely coopemtes in a substantial number of projects with Leiden University Hospital and with several other hospitals in the Netherlands and abroad. Many of the mults are obtained in close cooperation with other mearch groups as can be seen from the many joint publications. At the 25th anniversary there were over 1800 publications and the graduate staff consisted of 40 of whom 15 had a permanent assignment. Presently the research focus is on biochemical and pathophysiological aspects of cardiovascular medicine and rheumatoid arthritis. Research areas indude: lipid metabolism and atherosclerosis fibrinolysis and proteolysis pathophysiology of endothelial cells Fibrinolysis became a &us of the Institute's research in the early 1970s. At that time a general outline of the mechanism of fibrinolysis was known, but a great deal of the system as well as its role in health and disease remained obscurr. Over the years, a program was established to study the activatingand inhibiting pro-

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PREFACE

cesses as well as the dissolution of fibrin. Human tissue activator was isolated and purified, (pro-)urokinasewas found in blood. Other activating mechanisms related to pro-activator and Hageman Factor were studied. Inhibition of the activation steps as well as of the final process of dissolution of fibrin are an essential part of the program. A method for the measurement of plasminogen activator inhibition was established. Fibrinogen, fibrin and their degradation products are being studied, amongst others, with the aid of monoclonal antibody technology and on the basis of structure-function analysis. The stimulatingeffect of fibrin breakdown products on the activation process became well established. With all the above-mentioned knowledge the study of the regulation of fibrinolysis became possible. These studies took us into the field of Cellular Mechanisms. In the intact vascular tree the endothelium countcmcts coagulation by anticoagulant as well as profibrinolytic mechanisms. These processes have been studied in the Institute with particular emphasis on the synthesis and release of tissue-type plasminogen activator (tPA), a major regulator of the fibrinolytic system. tPA activity is tuned by plasminogen activator inhibitors, particularly PAI-1, which can also be produced by the endothelium. Regulation of this is also the subject of our investigations. Modulation of tPA production proved to be possible in our cell culture experiments, opening the road towards actively interfering in the body’s own fibrinolytic potential. Animal experiments are pertbrmed in order to study the pharmacological release of tPA; in addition thrombolysis models are in operation fbr studying thrombolytic agents. More generally, the pharmacology of fibrinolysis as well as drug delivery and dosage fbrms part of the research activities. The knowledge gathered is applied to clinical research. Our long-term aim is to learn enough about the mechanism of the process and its regulation to be able to use it effectively for the control of fibrinolysis. In view of the high prevalence of thromboembolic diseases and of a possible relationship between impairment of fibrinolysis and the development of arteriosclerosis this is of great importance. As hereditary fictors are involved we are also studying familial thrombosis at the molecular genetic level. The emphasis in the world on the study of fibrinolysis has been in particular on thrombosis and hemostasis. However, the importance of the central process in fibrinolysis, plasminogen activation, goes beyond this. It plays a role in growth, in development and in tissue repair. At the center of this mechanism is a glycoprotein, plasminogen, which is ubiquitously available in the body owing to its pnsence in blood. Activation of plasminogen leads to the formation of the very potent serine protease plasmin. The organism controls plasmin by several mechanisms, one of which is a specific inhibitor. This inhibitor is capable of neutralizing plasmin in what is recognized as one of the fistest interactions between biological molecules. On the other hand very intricate mechanisms make it possible for plasmin to digest fibrin and some other proteins in the body. Binding plasmin to substrate can protect it from inhibition by the inhibitor. In tissue repair and development striking similar mechanisms have been uncovered without the necessary presence of fibrin. Specific binding sites fbr plasminogen activation and plasmin enables these compounds to escape the blodtig action of inhibitors and to play a role in pathophysiology. The 25th anniversary of the Gaubius Institute provided a good opportunity to focus attention on the much wider implications of plasminogen activation than its role in fibrinolydvascular disease.

PIETERBRAKMAN CORNELIS KLUFT

Twenty-five years of the Gaubius Institute.

Preface Tbenty-five Years of the Gaubius Institute The Gaubius Institute was established by the University of Leiden in 1965 to provide a center fbr m...
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