RESEARCH AREAS WITHIN CEROSS
All CEROSS scientists work in close proximity at the Sahlgrenska Academy of Göteborg University. The consortium comprises experts in fields as diverse as molecular biology, genetics, physiology, pharmacology, epidemiology, urology, rheumatology, clinical immunology, psychiatry, gynecology, and internal medicine. By fostering the exchange of knowledge and ideas from different fields of medicine on the function of SS, by sharing sophisticated equipment and methodologies, and by providing access to populations that have been genotyped and characterized with respect to phenotype for different purposes, CEROSS has markedly enhanced the ability of its researchers to pursue related avenues of research. With its exceptional breadth in experimental and clinical research, the consortium is ideal for conducting translational research, enabling prompt testing of novel concepts in the clinical setting. It is also ideal for the training of young researchers, by giving them experience of different aspects of medical research, from molecular and preclinical studies to clinical drug trials and epidemiological approaches.
The major SS—testosterone, progesterone, and the estrogens—are key regulators of human reproduction. In addition, these hormones exert prominent influences on a variety of body organs and have been implicated in a number of widespread and disabling disorders.
The role of SS in osteoporosis, a major reason for ill-health among the elderly, is well established. Increasing evidence suggest that SS may be critically involved in rheumatoid arthritis, explaining the marked female preponderance in prevalence. Both androgens and estrogens may play a key role in the metabolic syndrome, including its features insulin resistance, type 2 diabetes, and cardiovascular disease, as illustrated, for example, by the fact that the polycystic ovary syndrome shares many traits with the metabolic syndrome. SS-related cancers, such as prostate cancer in men and breast cancer in women, are the leading causes of cancer-related death in Sweden. And the notion that SS play a critical role in brain function is clearly illustrated by conditions such premenstrual dysphoric disorder, perimenopausal depression, and postpartum depression, and is further supported by the alleged involvement of SS in disorders such as Alzheimer’s disease and autism.
Substantial progress has been made in understanding of the actions of SS on the molecular level. Subtypes of SS receptors have been identified, and the role of activated SS receptors as transcription factors has been elucidated. The importance of SS conversion in target tissues has been increasingly understood, knowledge of SS receptor co-modulators has expanded, and the functional consequences of certain polymorphisms in SS-related genes have been revealed. Yet there is an acute need for intensified research on how SS influence body function on different levels.
For example, in contrast to previous assumptions, large treatment studies now suggest that long-term hormone replacement therapy (HRT) for postmenopausal women causes more harm than benefit, with increases in the risk of stroke and breast cancer being the most alarming results. Although long-term HRT in elderly women has been questioned, estrogens clearly have beneficial effects on bone density and on symptoms associated with perimenopause. Moreover, HRT may have important positive long-term effects on health, including cognitive function and certain forms of cancer. A further consideration is the large percentage of women who are exposed to exogenous SS in the form of oral contraceptives.
From this perspective, the need for a deeper understanding of SS function is obvious. SS receptors are situated in a variety of organs, and SS probably play a role in many important disorders. Therefore, research on the effects of SS on the organism would benefit from adopting a global approach, taking all the different actions of SS into consideration (e.g., in developing and evaluating new treatment options). The need for such a global approach provided the major rationale for the formation of CEROSS.
THE ADDED VALUE OF CEROSS
The possibilities of rapidly increasing our knowledge in the SS area have been dramatically enhanced by the Human Genome Project and recent methodological achievements, including high-throughput genotyping, the use of genetically modified organisms, and DNA microarrays. CEROSS provides access to these and many other sophisticated tools and techniques, and facilitates the exchange of ideas, data, and research resources.
For example, when a member of the consortium develops a new strain of transgenic animal with altered expression of a SS-related gene, it can rapidly be used to address questions of importance for other members of CEROSS. Likewise, microarray experiments may yield additional information if the effects of SS on several different tissues are being analyzed in parallel and compared. And when a polymorphism in an SS-related gene of possible functional relevance is identified, researchers in different fields, with access to different patient populations, can collaborate to rapidly address its putative influence on different aspects of the human phenotype, confirming or calling into question its tentative functionality.
By combining experience from a variety of research fields, including metabolism, osteoporosis, neuroscience, immunology, and endocrine cancer, and by sharing techniques and strategies applicable to different lines of investigation, CEROSS researchers can substantially increase our understanding of how SS influence human health.
Several issues are especially important. Through what mechanisms do SS exert their influence on human diseases? Is it possible to define subpopulations of postmenopausal women who respond beneficially or negatively to long-term treatment with SS? What are the roles of SS receptor co-modulators in different tissues? Can we develop new drugs that selectively influence certain receptors or enzymes that may exert the beneficial but not the harmful effects of SS? What is the functional relevance of polymorphisms in SS-related genes to the disorders discussed above. These and other questions can be addressed most effectively by researchers coordinating their efforts within the consortium rather than working independently.
A particular strength of our consortium is the vast experience of its members in experimental research, including cellular studies and integrative physiology, and in clinical research, including genetic studies, clinical drug trials, and epidemiology. CEROSS researchers have, for example, access to DNA from several large and partly unique populations that are being investigated for possible influences of polymorphisms in SS-related genes on various aspects of the human phenotype. Moreover, they have considerable experience in studying transgenic mice in which the expression of SS receptors has been manipulated and in drug trials for SS-related conditions. Finally, CEROSS has excellent facilities for molecular and cellular research related to bone, metabolism, immunology, cancer, and neuroscience.
THE SCIENTIFIC STANDARD OF CEROSS
The combined competence within CEROSS has made the consortium one of the world’s leading centers for multidisciplinary, translational research on SS, with annual external funding of approximately 65 MSEK. In the last 5 years, CEROSS scientists published more than 475 peer-reviewed original papers. Many of the CEROSS publications are published in high-impact journals such as New England Journal of Medicine, Lancet, Science, Nature Genetics, Nature Medicine, Endocrine Reviews, Genes and Development, EMBO Journal, Journal of Clinical Investigation, PNAS, and Archives of General Psychiatry. CEROSS scientists have also been invited to speak at more than 200 international congresses. They have supervised 38 Ph.D. students who defended their thesis during the last 5 years and are currently supervising 44 Ph.D. students. During this period, 46 postdocs and guest researchers have been attracted to the different research groups.
All 10 senior researchers of CEROSS have published on the subject of SS. Dr. Ohlsson has worked extensively in this area, with a particular focus on osteoporosis. Dr. Holmäng has published many papers on the possible role of SS in metabolism. Drs. Tarkowski and Carlsten have studied the role of SS in rheumatic diseases. The focus of Dr. Damber’s research is SS-related cancer. Dr. Eriksson has long studied the influence of SS on the brain, including possible roles in psychiatric disorders. Dr. Billig is an expert on the physiology of the ovaries. Dr. Jansson has published extensively on the influence of SS on the secretion of growth hormone.
Shortly after CEROSS was founded, it became obvious that the consortium would be strengthened by adding a research group with expertise in epidemiology. To this end, Dr. Ingmar Skoog was recruited. In addition to his vast experience in epidemiology, he is in charge of several unique longitudinal population-based cohorts that will be of immense value for addressing various issues related to the possible influence of SS on susceptibility for common disorders. As a world-renowned expert in risk factors for dementia, Dr. Skoog is eminently suited to address the intriguing issue of the possible role of SS in the development of Alzheimer’s disease (AD), where estrogen has recently been attributed both protecting and harmful effects. Dr. Skoog was also part of a panel evaluating HRT for different disorders, organized by the Lancet, the British Medical Research Council, and the Harvard School of Public Health. (A report from the panel was published in Lancet in 1999) To gain additional competence in neuroendocrinology, CEROSS recruited Dr. Suzanne Dickson, an expert on the hypothalamus, a major brain target for SS. Dr. Dickson is also an expert in obesity and metabolism and is thus highly qualified to contribute to efforts within CEROSS to elucidate the role of SS in the metabolic syndrome. Although Drs. Skoog and Dickson had not previously focused on SS, their recruitment markedly enhanced the competitiveness of CEROSS. Both are now deeply involved in SS-related research.