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Endocrinology and Neuro-Endocrine Immunology
Theme 1: Endocrinology and Ageing
All subthemes of ‘Endocrinology and Ageing’ try to implement their basic research data from the bench in the patient and the population, while at the same time answering the questions from studies in the population by working at the bench.
Keeping a constant eye on the clinical relevance of basic research for the patient and population at large and vice versa, has positioned these themes at a recognized high level in the scientific community, as can be demonstrated by e.g. the scientific output and obtained grants, both from national and international sources. In the following pages, each of the themes is described in more detail.
Subtheme 1: Neuro-endocrinology
Prof. dr. L.J. Hofland, Dr. F.J.W. Koper, Dept. of Internal Medicine; Section of Endocrinology, Prof. dr. Dr. E.P. Krenning, Dept. of Nuclear Medicine; prof. dr E.F.C. van Rossum, Prof. dr. Dr. S.W.J. Lamberts and Prof. dr. Dr. A.J. van der Lely, Dept. of Internal Medicine; Section of Endocrinology
This subtheme studies disorders in neuro-endocrinology, neuro-immunology and endocrine oncology. It develops new modalities for molecular imaging and treatment using peptide receptors as primary targets and aims to unravel the endocrine and immunological basis of important diseases in the community.
In particular, the research includes the following main topics:
- Pituitary adenomas (Prof. dr. L.J. Hofland): Pituitary adenomas cause severe clinical syndromes due to hormonal overproduction by the adenoma cells. Striking examples are acromegaly due to a GH secreting pituitary adenoma and Cushing’s disease due to excessive ACTH secretion by a pituitary adenoma. The search for novel medical therapies for these diseases is one of our main aims.
- Neuroendocrine tumors (NET) (Prof.dr. L.J. Hofland): Most NET cells express peptide hormone receptors. Such receptors can be used as molecular targets for diagnosis and therapy. The most striking example is the localization and treatment of neuroendocrine tumors using radionuclide coupled peptide somatostatin analogs. Apart from somatostatin receptors, also other peptide hormone receptors are expressed on tumors, such as bombesin receptors on prostate- and breast cancer. The expression of peptide hormone receptors on tumors and the role of radiolabeled peptides in the in vivo localization and treatment of tumors is studied.
- Ghrelin (Prof. dr. A.J. van der Lely): We have discovered that ghrelin can influence insulin sensitivity and that its unacylated form can significantly improve insulin sensitivity by antagonizing the acylated form of ghrelin, which makes the combination a candidate for treatment of the many disorders which can be characterized by an increased insulin resistance. Studies on the metabolic activities of ghrelin and the role of ghrelin receptors herein form a main arm of the current research activities.
- Glucocorticoid receptors (Dr F.J.W. Koper, prof. dr. E.F.C. van Rossum): We identified a number of polymorphisms in the glucocorticoid receptor (GR)-gene that are associated with changes in the glucocorticoid sensitivity. A main research goal is the identification of the effects of these variations on numerous aspects of health and ageing.
- Cortisol in relation to cardiometabolic diseases and psychiatric diseases (prof. dr E.F.C. van Rossum, Dr F.J.W. Koper): We are one of the few laboratories in the world who developed an innovative method to determine long-term cortisol levels using scalp hair. Studying relations between the stress hormone cortisol and the metabolic syndrome, cardiovascular disease, mental illnesses and numerous other disease was previously limited by the only available highly variable point measurements in e.g. blood and saliva. In contrast, our novel cortisol analysis in hair resulted in numerous promising insights in these stress-related diseases and yielded many possibilities to study other diseases or conditions, which are related to cortisol. Most of the findings are directly relevant for clinical practice.
- Insulin-like growth factor I (IGF-I): We recently studied genetic polymorphisms in the regulatory region of the IGF-I gene and found that both the risk of type 2 diabetes and myocardial infarction were significantly increased in non-carriers of a 192-bp allele when compared with carriers of this polymorphism. This suggests that a genetically determined exposure to low IGF-I levels plays a role in the pathogenesis of both type 2 diabetes as well as myocardial infarction. Considering the high complexity of the IGF-I system, which includes many binding proteins, we have now developed an IGF-I bioassay to determine more in detail the role of genetic variations in the IGF-I gene in relation to circulating IGF-I bioactivity.
- Peptides and their receptors in immune disease: We have found that peptide receptors for somatostatin are expressed on normal immune cells, as well as on activated lymphocytes and monocytes in affected tissues of patients with rheumatoid arthritis and patients with granulomatous disease. An important line of research is to investigate the potential role of somatostatin analogs (unlabeled, radiolabeled-, or labeled with photosensitizers) in the treatment of various types of immune disease.
Subtheme 2: Role of the thyroid gland in disease
Prof. dr. T.J. Visser, PhD, Department of Internal Medicine, Section of Endocrinology
Prof. dr. R.P. Peeters, Department of Internal Medicine, Section of Endocrinology, Rotterdam Thyroid Center
Thyroid hormone (TH) is crucial for normal development and tissue function. Its actions are mediated via binding to nuclear TH receptors (TRs), encoded by the THRA and THRB genes. It is known for decades that inactivating mutations in THRB result in a well-documented clinical syndrome of TH resistance. Ever since the characterization of the THRA gene in 1987, investigators have searched for patients with mutations in TR. This was without success until we and others recently identified the first patients with a defective TR1, suffering from marked growth retardation, mild cognitive defects, and biochemical alterations resembling those in patients with combined pituitary hormone deficiency (van Mullem et al, NEJM 2013).
Our group currently studies this newly discovered clinical phenotype in detail. The overall approach includes: 1) identification and characterization of new patients with mutations in THRA, 2) elucidation of the molecular mechanisms causing the phenotype of patients with a mutation in TR1. By combining clinical data from patients with mutations in THRA with animal data and in vitro data from transfected cells, we will obtain important new insights into the mechanisms underlying this new clinical syndrome. Identification of additional patients with mutations in THRA is of crucial importance because current evidence predicts that these patients will benefit from treatment with TH, which is easily available and costs only €30 per year.
Additional studies of our group focus on genetic defects in other TH pathway genes, such as TH transporters. Since the action of T3 is large exerted by binding to nuclear receptors, transport of T4 and T3 across the plasma membrane by specific transporters is required.
Recent studies in our lab have identified two members of the monocarboxylate transporter family, MCT8 and MCT10, as active and specific thyroid hormone transporters. The pivotal importance of MCT8 has been demonstrated by our identification of mutations therein in patients with severe psychomotor retardation and abnormal thyroid hormone levels. Thyroid hormone is crucial for normal brain development, and mutations in MCT8 are believed to impair T3 uptake in central neurons, leading to the defect in neurological development. Similar abnormalities in brain thyroid hormone homeostasis may result from mutations in other TH pathway genes, such as those coding for MCT10, or the enzymes involved in intracellular metabolism of TH (deiodinases).
We have started a large study aimed at identification and characterization of mutations in thyroid hormone-related genes in patients with psychomotor retardation and abnormal thyroid parameters. Aspects of this study range from clinical to very basic. If you wish to read more about deiodinases and transporters and our recent work in patients with psychomotor retardation, see our recent review (Visser et al. Mol Endocrinol 2011; 20: 1-14).
Subtheme 3: Calcium and Bone related research
Prof. dr. A.G. Uitterlinden, Department of Internal Medicine, Section of Endocrinology
Calcium and bone metabolism research focuses on the regulation of skeletal and calcium homeostasis and the development and progression of diseases in particular during ageing. The eventual goal is by integration of molecular and cell biological, experimental animal models, epidemiological and genetic epidemiological and clinical research to achieve improved diagnostics and treatment of skeletal diseases and disturbances in calcium metabolism. The current therapies for osteoporosis are predominantly directed to inhibit bone resorption and thereby progression. There is, however, a great need for anabolic therapies that stimulate bone formation because bone loss has already occurred at the moment that the consequences of osteoporosis become overt. In line with this, the improvement of early diagnosis is of great importance.
Four major interrelated research lines directed to etiology, diagnostics and treatment of calcium and bone related diseases can be identified.
- Molecular mechanisms of bone cell differentiation and regulation of bone formation and resorption. The aim is:
- to identify novel therapeutic targets and therapies for osteoporosis and to obtain new insights into mesenchymal stem cell differentiation important for tissue engineering, and
- to assess new leads for the identification and characterization of risk determinants (see Research line 2) by genomic and proteomic approaches.
- Identification and characterization of risk determinants for osteoporosis.
- to analyse genes/proteins identified in Research line 1 as risk determinants, and
- to identify new markers by serum protein profiling of individuals with specific osteoporotic characteristics (e.g. fractures).
This research can be perfectly coupled to the genome wide association studied that are planned to be performed within the Rotterdam Study.
- Relationship of osteoporosis and osteoarthritis and the significance for development of osteoarthritis.
In the clinic severe forms of osteoporosis and osteoarthritis seem to exclude each other, however, there also seem to be overlapping aetiological mechanisms. The aim is to include in the research lines 1 and 2 also the osteoporosis — osteoarthritis relationship and to assess differences but also to analyse common mechanisms.
- Calcium homeostasis in relation to bone metabolism and osteoporosis.
The aim is to investigate changes in calcium homeostasis and bone metabolism during aging by human population and experimental animal studies. The combination of human population and experimental animal studies provide the opportunity to analyse the epidemiological observations at a more mechanistic level. These studies will provide new insights into the calcium and skeletal homeostasis and potential novel therapeutic and diagnostic targets which are coupled to research lines 1 and 2.
Subtheme 4: Metabolism and Reproduction
Dr.ir. J.A. Visser, Prof. dr. A.J. van der Lelij, Dept. of Internal Medicine; Section of Endocrinology
The research of the Metabolism and Reproduction group is directed at gonadal and metabolic dysfunction. Through a combination of physiological, genetic and signal transduction studies our group aims to understand the role of steroid hormones, peptide hormones, and growth factors in the interaction between gonadal function and metabolism (such as reproductive aging, PCOS) and metabolism (including metabolic aging). The hormones studied include estrogens, androgens and glucocorticoids, ghrelin and unacylated ghrelin, and TGFβ family members such as anti-Müllerian hormone and bone-morphogenetic proteins. An important focus of our studies is on white and brown adipose tissue functioning, insulin sensitivity and lipids.
Additionally, we aim to understand the sex differences in metabolic dysfunction. The ultimate goal is to unravel the mechanisms by which hormones and growth factors contribute to metabolic disorders, such as obesity, diabetes, and cardiovascular disease in order to identify novel risk markers and novel therapeutic targets.
Within our group we have three interrelated research lines. All lines use a combination of molecular, cellular and animal research and studies in humans.
- The sex-specific regulation of the activity of fat metabolism (Dr. Aldo Grefhorst & Dr. ir. Jenny A. Visser).
There are clear differences between men and women in fat distribution and the development of obesity and associated metabolic diseases. This suggests that sex-specific approaches may be needed to combat obesity and associated diseases. By detailed investigation of the differences between male and female metabolism and the role of sex steroids herein, we aim to understand sex differences in metabolism, especially in the white adipose tissue (WAT), brown adipose tissue (BAT) and the liver. We and others have shown in animal experiments that females have more active BAT than males. Furthermore we recently showed that the TGFβ family member BMP8b might be involved in this sex-difference in BAT activity, because BAT of female mice had a higher BMP8b expression than BAT of male mice. Since the brain plays an important role in the regulation of metabolism, we also study how sex steroids act in the brain to control the function of peripheral metabolic tissues.
- The development of un-acylated ghrelin (UAG) as a drug to combat obesity and its accompanying physiological aberrations (Dr. Patric Delhanty & Prof. dr. Aart Jan van der Lely).
The acylated form of ghrelin (AG) is known as the hunger hormone that induces obesity and insulin resistance. Un-acylated ghrelin (UAG) is the naturally occurring non-acylated form of ghrelin and an increasing number of studies suggest that UAG is a functional inhibitor of AG. An analogue of UAG is currently in phase I clinical trials to discover if it can reverse the effects of obesity and/or diabetes. However, despite evidence for biological activity of UAG on various cell types and in animals and humans, and that inhibition of a range of signaling pathways block its activity, we still do not know its precise mechanism of action, since a receptor for UAG has not yet been discovered. One of our main ongoing research themes is to investigate the mechanism of action of UAG and its analogues in animal models of obesity and insulin resistance, as well as mice that have had the ghrelin gene deleted. The goal is to identify discrete physiological effects which could impact on these pathologies, such as effects on energy metabolism, as well as sites of action, for example the pancreas, adipose tissue and brain.
The goal here is to more precisely define the biological function of UAG and give clues to its mechanism of action. An important related research aim is to discover the UAG receptor using cell-lines known to respond to UAG. Approaches we are using include investigation of signal transduction pathways, receptor-ligand interactions and proteomic techniques.
- The interaction between female fertility and metabolism (Dr. ir. Jenny A. Visser)
This research line focuses on the regulation of ovarian function and the interaction with metabolism as in reproductive aging and polycystic ovary syndrome (PCOS). Ovarian folliculogenesis is a dynamic process that declines with increasing age ultimately resulting in menopause.
Menopause not only leads to a loss of estrogens but also of ovarian growth factors. In contrast, in PCOS ovarian production of androgens and growth factors is increased. Both conditions, menopause and PCOS, are associated with an increase in metabolic risk factors. Using mouse models with altered gonadal function (AMH knockout mice, DHT-induced PCOS mouse model), we have recently shown that gonadal growth factors regulate the function of white and brown adipose tissue and lead to sex-specific differences in glucose tolerance. The aim of our studies is to understand the underlying mechanisms by which gonadal growth factors contribute to the (sex-specific) regulation of metabolism and to identify the gonadal factors involved.
MSc. students who are interested to participate in one of the research lines of the subthemes of ‘Endocrinology and Ageing’ are encouraged to contact one of the working group leaders.
Theme 2: Neuro-Endocrine Immunology
Autoimmune diseases of the neuro-endocrine system are leading causes of morbidity, psychosocial burden and economic loss in our western society. Neuro-endocrine autoim-mune diseases in which the Dept. of Immunology is in particular interested are type I dia-betes (T1D), autoimmune thyroid diseases (AIT), multiple sclerosis (MS), Guillain-Barré syndrome (GBS) and systemic sclerosis). Other autoimmune diseases of interest are rheumatoid arthritis (RA), Sjögren syndrome and psoriasis. The Dept. also studies diseases, which are related or associated to these autoimmune diseases, such as bipolar disorder (BD), other mood disorders (major depressive disorder, MDD; post partum psychosis, PPP), and schizophrenia (SCZ). The premise is that an activated inflammatory response system (IRS) drives all these pathologic processes, yet differences occur between these complex diseases due to a difference in eliciting or protecting co-factors of genetic and environmental character, such as e.g. the polymorphisms in the HLA system, iodine consumption, smoking, gut infections, pregnancy and stress. The neuro-endocrine system is an important regulator of the IRS, both via the HPA-axis and the vagus nerve.
In the research the Dept. of Immunology predominantly focusses:
- On aberrant pro- and anti-inflammatory set points of monocytes/macrophages/dendritic cells and of Th1, Th17 and T regulatory cells as important causes of the activation of the IRS. Aberrations of these cells are studied in T1D, AIT, BD, MDD, PPP, SCZ, MS and atherosclerosis. At present a large scale EU program (19 partners from 10 EU countries.) is coordinated by Prof Drexhage, which has as short title MOODINFLAME and this program views mood disorders as ‘low-grade special inflammations of the brain’.
- On molecular mimicry between auto-antigens and environmental antigens as another important cause of autoimmune diseases, such as GBS.
- On abnormal interactions between inflammatory cells/antibodies and the fibroblast, leading to abnormal fibrotic processes, such as in systemic sclerosis and Graves’opthalmopathy.
Further focuses are the amelioration of MS, AIT and RA during pregnancy, the exacerbation of these diseases and of mood disorders in the post-partum period and the immune regulation exerted by pregnancy-related and lactation related hormones and peptides. Our research covers a broad area ranging from patient cohort studies via functional in vitro and genetic analyses of patient material to several animal disease models in rodents and non-human primates.
Via our research we hope to develop better diagnostic procedures and treatment modalities. We perform our research in close collaboration with clinical researchers who are well trained in immunology, endocrinology and neuroscience. This allows the joint construction of scientifically relevant research questions and well-characterized patient cohorts.
Subtheme 1: The immunology of endocrine autoimmune diseases, major psychiatric diseases and atherosclerosis
Dr. M. Versnel and dr P. Leenen (Autoimmune Unit, Dept. of Immunology, Erasmus MC)
In our research over the past 5-10 years we have identified various functional abnormalities of monocytes/macrophages/dendritic cells and T cells in T1D, AIT and Sjögren syndrome. This research was performed on patient materials (serum and leukocyte preparations) and — in parallel — in animal models of these autoimmune diseases, in particular the NOD mouse and the BB-DP rat. We have also assessed the role of these monocyte/macrophage/dendritic cell and T cell abnormalities in defective tolerance induction.
In our research we also found a heightened risk for T1D and AIT in bipolar disorder patients and their family members (twins and children) and vice-versa, e.g. more mood disorders in patients with AIT and T1D. It is also known that endocrine autoimmune diseases and mood disorders are associated with a higher risk for atherosclerosis. Our studies and observations thus pointed in the direction of a shared vulnerability factor for endocrine autoimmune diseases, mood disturbances and atherosclerosis. We presently study the combination of a pro-inflammatory activated monocyte/macrophage/dendritic cell system, an activated T helper cell system and a defective regulator cell system as the shared abnormal vulnerability factor between mood disorders, autoimmunity and atherosclerosis. In the latter in-flammatory disorder we also focus on special descendents of the monocytes, i.e. the endothelial precursor cells.
To approach the problem on a molecular level we have identified genes aberrantly ex-pressed in monocytes of T1D, AIT, SCZ, MDD, PPP and BD patients. These gene products are linked to the previous found functional monocyte abnormalities and around 50 key aberrant genes have now been selected. We have designed custom made (RQ-PCR) arrays for these genes and test the ability of these arrays to distinguish in the lab various subtypes of T1D, to identify pre-diabetic individuals and individuals at risk for the development of MDD and SCZ.. We also target these key molecules with novel drugs (anti-cytokines, 2nd generation COX-2 inhibitors, KMO-inhibitors) in an attempt to correct the pro-inflammatory set point of the immune system to lower the risk for the development of the afore-mentioned diseases.
Subtheme 2: Pathogenesis of the Guillain-Barré syndrome
Dr. B.C. Jacobs (Depts. of Neurology and Immunology, Erasmus MC) and Prof. dr. J.D. Laman (Unit Immune regulation, Dept. of Immunology, Erasmus MC)
The Guillain-Barré syndrome (GBS) is the most common form of acute neuromuscular pa-resis. Patients with GBS have a rapidly progressive immune-mediated neuropathy result-ing in severe paresis of limb and respiratory muscles, from which patients may die. Re-search in our group showed that GBS is a molecular mimicry mediated disease in which preceding infections trigger the production of toxic cross-reactive antibodies to neural structures. In about 40% of patients these antibodies are directed to neural glycolipids or gangliosides. Campylobacter jejuni is the predominant cause of infection in GBS and lipo-oligosaccharides from these bacteria indeed exactly mimic gangliosides. Infusion with immunoglubulins is an effective treatment in GBS, although the mechanism of action of this treatment is unknown.
Four important issues remain unsolved in GBS:
- What are the immuno-targets in patients without anti-ganglioside antibodies? Pilot studies have identified new targets, but these need to be tested in the available large cohorts of patients, in relation to neurological deficits and prognosis.
- What is the cellular mechanism driving the production of these cross-reactive anti-bodies? Our recent studies indicate that C. jejuni directly activates dendritic cells and B-cells. This in vitro model for GBS will therefore enable us to determine the responsi-ble cellular pathways.
- Can genetic host factors explain why only 1 in 1000 persons with a Campylobacter infection develops GBS? We are studying single nucleotide polymorphisms in immune response genes, which may determine this abnormal response to infection.
- Which mechanism of action is responsible for the therapeutic effect of immu-nogloblulins? Several serological and cellular models have been developed to identify the effective fractions of these immunoglobulins and clarify the mechanisms of action.
At the Erasmus MC there is a unique collaboration between the departments of Neurology, Immunology, Medical Microbiology & Infectious Diseases regarding GBS research. Central to this collaboration is the patient-related laboratory research, which gives us excellent opportunity to address these four study objectives and in which students are gladly invited to participate.
Subtheme 3: Central Nervous system inflammation and MS
Prof. dr. J.D. Laman (Unit Immune regulation, Dept. of Immunology, Erasmus MC)
Inflammation plays a role in most neuro-degenerative diseases. The sub-unit Central Nervous System (CNS) Inflammation of the Erasmus MC originates from the clinical and scientific focus on multiple sclerosis (MS). MS is the most common cause of neurological disability in young people in the European community. Many inflammatory CNS disorders can mimic MS, such as viral infections (meningoencephalitis), systemic autoimmune diseases (SLE, Sjögren syndrome), sarcoidosis and neurobehçet.
Despite distinct pathologies in the clinical array of these CNS disorders, several common pathways appear to exist. In MS it is probably a myelin directed T- and B-cell mediated autoimmune process that stands at the base of the pathology. MS is caused by a fatal interaction of yet poorly identified genes (e.g. HLA) with environmental factors (viral infections, specifically EBV, vitamin D and perhaps smoking).
Aim of this program is to enhance insight in the different routes that lead to white matter inflammation as well as neuronal and axonal damage, mainly using MS as a model.
The unit has a strong focus on biology and translational medicine, with a general theme around ‘Biological determinants of the disease course’. Intense collaborations exist within the following areas: Clinical Neurology, Immunology, Genetics, Epidemiology, Virology, MRI and Proteomics. Clinical material consists of data and samples from various cohorts as well as DNA of Dutch multiplex MS families and a unique family with 26 persons suffer-ing from MS, which is the largest MS pedigree in the world. In addition, post mortem tissue of brain and lymph node of MS patients is readily available.
Subtheme 4: Systemic sclerosis, endocrine ophtalmopathy, inflammation and fibrosis
Dr. P.L.A. van Daele, dr. W. Dik, dr. M. Versnel, Prof. dr. H. Hooijkaas, (Department of Internal Medicine, Section of Clinical Immunology and Department of Immunology)
Inflammatory reactions are normally resolved in a phase of scar formation involving the activation of fibroblasts. Fibroblasts are anyway involved in the inflammatory process by providing a scaffold for the inflammation. In addition there is an intensive molecular cross talk between tissue fibroblasts and resident and infiltrating immune cells during the inflammatory process. In certain immune pathological conditions these interactions are aberrant and result in abnormal inflammation and fibrosis, e.g. during systemic sclerosis and endocrine ophtalmopathy. Excessive fibroblast activation may also play a role in liver cirrhosis and in fibrosis following rejection after kidney transplantation.
The first two conditions (systemic sclerosis and endocrine ophtalmopathy) are our current models for further study, focusing on receptor antibodies and other immune stimulators for fibroblasts and the resulting stimulation of kinase pathways in fibroblasts. Attempts are made to intervene in such pathways (both clinically and in the laboratory) with kinase inhibitors such as Imatinib mesylate, AMN107 and Dasanitib.