Dr. Monika Ehrhart-Bornstein (passed away)
Research in our group focuses on basic mechanisms and clinical implications of cellular crosstalk in endocrine tissues and interactions between different endocrine systems, adipose tissue, and the immune system.
1. Adrenal Gland Tumorigenesis
For over a decade one of our main interests is on adrenal tumors and pre-clinical adrenal cancer models, with special focus on pheochromocytoma (PHEO). Based on initial in vitro studies we developed a novel mouse pheochromocytoma (MPC)-mcherry allograft model enabling in vivo-fluorescence imaging of tumor development. Here, as the first group so far, we could correlate tumor size with tumor-related renal monoamine secretion in preclinical PHEO models. Our actual ongoing studies (Christian Ziegler) now evaluate combined and novel treatment strategies for PHEO based on our subcutaneous mcherry mice and on recently developed advanced bioluminescence PHEO models with different organ lesions, typical for the human disease. Importantly, our model to some extent recapitulates the human situation with regard to the catecholamine secretion pattern and very high density of somatostatin 2 receptor (SST2) expression. The latter was recently found to be also true for human PHEOs with a high metastatic risk due to SDBH mutations.
2. Adrenal Gland Insufficiency
Adrenal insufficiency is a life-threatening disorder that requires a complex and permanent hormone replacement. All current replacement strategies suffer from numerous problems as they fail to restore circadian variations in hormone secretion. Therefore, adrenal cell transplantation could be a preferable therapeutic alternative for patients suffering from primary adrenal dysfunction. However, this strategy is critically limited by the lack of suitable donors of human organs and the requirement of chronic immunosuppression. Transplantation of immunoisolated xenogeneic adrenal cells could and would be a promising alternative for these patients. The present project (Mariya Balyura) utilizes latest technologies of cell encapsulation in order to renew the idea of adrenal cell replacement to generate a bioartificial adrenal transplant for safe and physiological hormone substitution.
3. Critical illness-mediated Adrenal Gland Dysfunction
In many critically ill patients, this homeostatic activation of the adrenal gland hormone production is impaired, although the mechanisms are mostly unknown. In our previous studies (Waldemar Kanczkowski), we demonstrated that both endotoxemia-provoked SIRS and cecal ligation and puncture (CLP)-induced sepsis lead to systemic and adrenal gland inflammation which was associated with rapid immune cell infiltration and onset of cellular death of adrenal cells. Furthermore, by engaging mice with tissue-specific inactivation of TLR signaling, we identified myeloid cells in the adrenal gland microenvironment as being crucially involved in hypothalamic-pituitary-adrenal (HPA) axis activation and adrenal inflammation. Currently our work is focused on the role of tissue-restricted TLR signaling, immune cell infiltration, mitochondria function and dysfunction in the adrenal gland inflammation and cell death. We also designed and imply novel anti-inflammatory and mitochondria-targeted therapeutic interventions in the resolution of adrenal inflammation and prevention of cell death. With these approaches we will better understand the underlying mechanisms involved in sepsis-mediated adrenal gland deregulation and identify novel therapeutic interventions in sepsis treatments.
4. Progenitor Cells in the Adrenal Gland
The adrenal gland is a highly plastic organ with the capacity to adapt the body homeostasis to different physiological needs. Recently we identified and characterized in mice a pool of multipotent nestin-gfp positive glia-like progenitor cells, which contributes to the plasticity of the adrenal gland. In addition, we found that nestin progenitors from the adrenal medulla are actively involved in the stress response by supporting and giving rise to chromaffin cells. Adrenal cortex also plays a major role in stress response. We observed that nestin-positive cells are also present in the adrenal cortex of our nestin-gfp transgenic mice. Therefore our aim in the present project (Charlotte Steenblock) is to define and characterize the nestin-gfp positive cell population located in the adult adrenal cortex.
5. Endocrine Function of Adipose Tissue
In Westernized countries overweight and obesity have reached epidemic proportions with dramatic medical consequences. Obesity is a major risk factor for lipid abnormalities, atherosclerosis, type 2 diabetes mellitus, heart failure and high blood pressure. The adipocyte has long been suggested to be directly involved in the body’s homeostasis and recent evidence now proves that adipose tissue is a highly active endocrine organ. We therefore test the hypothesis that adipose secretory factors directly influence the body’s endocrine system and consequently are responsible for some of the medical problems associated with overweight. In this context we could show that factors secreted from human adipocytes directly inhibit cardiac contraction. We identified adipocyte fatty acid-binding protein (FABP4) as the main cardiodepressive factor released from adipocytes. Further studies suggest that FABP4 is a key molecule in linking obesity with atherosclerosis and diabetes mellitus. This project (Valéria Lamounier-Zepter) aims the development of new therapeutic strategies for metabolic and cardiovascular disorders related to obesity targeting FABP4.
• Ullrich M, Bergmann R, Peitzsch M, Zenker EF, Cartellieri M, Bachmann M, Ehrhart-Bornstein M, Block NL, Schally AV, Eisenhofer G, Bornstein SR, Pietzsch J, Ziegler CG. Theranostics, 2016.
• Jennewein C, Tran N, Kanczkowski W, Heerdegen L, Kantharajah A, Dröse S, Bornstein S, Scheller B, Zacharowski K. Mortality of Septic Mice Strongly Correlates With Adrenal Gland Inflammation. Crit Care Med. 2016;44:e190-9.
• de Celis MF, Bornstein SR, Androutsellis-Theotokis A, Andoniadou CL, Licinio J, Wong ML, Ehrhart-Bornstein M. The effects of stress on brain and adrenal stem cells. Mol Psychiatry. 2016
• Niehage C, Karbanová J, Steenblock C, Corbeil D, Hoflack B. Cell surface proteome of dental pulp stem cells identified by label-free mass spectrometry. PLoS One, 2016
• Rubin de Celis MF, Garcia-Martin R, Wittig D, Valencia GD, Enikolopov G, Funk RH, Chavakis T, Bornstein SR, Androutsellis-Theotokis A, Ehrhart-Bornstein M. Multipotent glia-like stem cells mediate stress adaptation. Stem Cells. 2015
• Balyura M, Gelfgat E, Ehrhart-Bornstein M, Ludwig B, Gendler Z, Barkai U, Zimerman B, Rotem A, Block NL, Schally AV, Bornstein SR. Transplantation of bovine adrenocortical cells encapsulated in alginate. Proc Natl Acad Sci U S A. 2015.
• Kanczkowski W, Sue M, Zacharowski K, Reincke M, Bornstein SR. The role of adrenal gland microenvironment in the HPA axis function and dysfunction during sepsis. Mol Cell Endocrinol. 2015;408:241-8.>
• Lamounier-Zepter V, Look C, Schunck WH, Schlottmann I, Woischwill C, Bornstein SR, Xu A, Morano I. Interaction of epoxyeicosatrienoic acids and adipocyte fatty acid-binding protein in the modulation of cardiomyocyte contractility. Int J Obes (Lond), 2015.
• Ullrich M, Bergmann R, Peitzsch M, Cartellieri M, Qin N, Ehrhart-Bornstein M, Block NL, Schally AV, Pietzsch J, Eisenhofer G, Bornstein SR, Ziegler CG. In vivo fluorescence imaging and urinary monoamines as surrogate biomarkers of disease progression in a mouse model of pheochromocytoma. Endocrinology 2014.
• Baessler A, Lamounier-Zepter V, Fenk S, Strack C, Lahmann C, Loew T, Schmitz G, Blüher M, Bornstein SR, Fischer M. Adipocyte fatty acid-binding protein levels are associated with left ventricular diastolic dysfunction in morbidly obese subjects. Nutr Diabetes, 2014.
• Schlottmann I, Ehrhart-Bornstein M, Wabitsch M, Bornstein SR, Lamounier-Zepter V. Calcium-dependent release of adipocyte fatty acid binding protein from human adipocytes. Int J Obes (Lond), 2014.
• Steenblock C, Heckel T, Czupalla C, Espírito Santo AI, Niehage C, Sztacho M, Hoflack B. The Cdc42 guanine nucleotide exchange factor FGD6 coordinates cell polarity and endosomal membrane recycling in osteoclasts. J Biol Chem. 2014
• Kanczkowski W, Alexaki VI, Tran N, Großklaus S, Zacharowski K, Martinez A, Popovics P, Block NL, Chavakis T, Schally AV, Bornstein SR. Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation. Proc Natl Acad Sci U S A. 2013;110:14801-6
• Ziegler CG, Ullrich M, Schally AV, Bergmann R, Pietzsch J, Gebauer L, Gondek K, Qin N, Pacak K, Ehrhart-Bornstein M, Eisenhofer G, Bornstein SR. Anti-tumor effects of peptide analogs targeting neuropeptide hormone receptors on mouse pheochromocytoma cells. Mol Cell Endocrinol. 2013.
• Kanczkowski W, Chatzigeorgiou A, Grossklaus S, Sprott D, Bornstein SR, Chavakis T. Role of the endothelial-derived endogenous anti-inflammatory factor Del-1 in inflammation-mediated adrenal gland dysfunction. Endocrinology. 2013;154:1181-9
• Engeli S, Utz W, Haufe S, Lamounier-Zepter V, Pofahl M, Traber J, Janke J, Luft FC, Boschmann M, Schulz-Menger J, Jordan J. Fatty acid binding protein 4 predicts left ventricular mass and longitudinal function in overweight and obese women. Heart. 2013.
• Kanczkowski W, Tymoszuk P, Ehrhart-Bornstein M, Wirth MP, Zacharowski K, Bornstein SR. Abrogation of TLR4 and CD14 expression and signaling in human adrenocortical tumors. J Clin Endocrinol Metab. 2010;95:E421-9.
• Ziegler CG, Brown JW, Schally AV, Erler A, Gebauer L, Treszl A, Young L, Fishman LM, Engel JB, Willenberg HS, Petersenn S, Eisenhofer G, Ehrhart-Bornstein M, Bornstein SR.Expression of neuropeptide hormone receptors in human adrenal tumors and cell lines: antiproliferative effects of peptide analogues. Proc Natl Acad Sci U S A. 2009.
• Lamounier-Zepter V, Look C, Alvarez J, Christ T, Ravens U, Schunck WH, Ehrhart-Bornstein M, Bornstein SR, Morano I. Adipocyte fatty acid-binding protein suppresses cardiomyocyte contraction: a new link between obesity and heart disease. Circ Res, 2009.