KFO 252:  Microenvironment of the Adrenal in Health and Disease

• Subject Area: Medicine
• Term: from 2011 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 189897882

The adrenal gland occupies a central position in the epidemic of stress-related disorders, including metabolic and cardiovascular diseases, which together comprise an increasingly overwhelming burden to health care systems of Western Societies. Adrenal gland-derived mineralocorticoids, glucocorticoids, androgens and catecholamines play diverse roles in obesity, diabetes and cardiovascular disease. Additionally, a correctly functioning adrenal is crucial to coping with perturbations to physiology, including detrimental systemic inflammation as in sepsis and the systemic inflammatory response syndrome (SIRS). Also of importance are the bidirectional links between adrenal gland dysfunction and metabolic, cardiovascular and inflammatory diseases. On the one hand adrenal dysfunction may be caused by the aforementioned diseases, while on the other hand may not only modulate outcome of metabolic, cardiovascular and inflammatory diseases but may also represent a significant contributing element or even the primary etiologic factor.Dissecting the adrenal microenvironment is imperative to any effort for understanding the bidirectional links between adrenal dysfunction and metabolic, cardiovascular and inflammatory diseases. Only a comprehensive understanding of the complexity of the adrenal microenvironment, along with its responses and adaptation to external stimuli, can enable the basis of stress-related disorders to be fully understood. Indeed our coordinated research efforts within the first funding period have focused predominantly on the molecular mechanisms underlying fine regulation of the cellular crosstalk within the adrenal microenvironment. This covers two broad areas: (i) mechanisms of adrenal hyperfunction in the context of adrenal hyperplasia and tumourigenesis, bridging concepts of genes, development, and tumour formation with metabolic dysregulation; and (ii) mechanisms of adrenal hypofunction, due to genetic disorders or in the context of inflammation and sepsis.Our research over the first funding period resulted in significant new findings related to adrenal hyperfunction and tumour formation as well as interactions between adrenal chromaffin, cortical, immune and vascular cells within the adrenal microenvironment in the context of adrenal hypofunction. We have also established unique and valuable platforms and toolboxes for experimental model systems, analytical methods as well as patient cohorts, datasets and clinical materials (biobanks) to support continuation of our efforts into the second funding period. These efforts will involve several linked and coordinated areas: (i) functional dissection of the adrenal microenvironment in both our experimental model systems and patient cohorts; (ii) development of new and improved diagnostic tests for adrenal disorders; (iii) manipulation of specific components of the microenvironment in murine models including specific inactivation of individual genes in distinct cellular populations (adr

• DFG Programme: Clinical Research Units

Projects

• Central administration: analytical, clinical and model systems platforms (Applicants Bornstein, Ph.D., Stefan R. ;  Chavakis, Triantafyllos ;  Eisenhofer, Ph.D., Graeme )
• Chromaffin progenitor cells in adrenal tissue formation (Applicants Androutsellis-Theotokis, Ph.D., Andreas ;  Ehrhart-Bornstein, Monika )
• Dissecting the adrenal-endothelial-immune interface in systemic inflammation: Implications for inflammationrelated adrenal dysfunction (Applicant Chavakis, Triantafyllos )
• Engraftment, function and beta cell regulation in the adrenal transplant model (Applicants Ludwig, Barbara ;  Morawietz, Henning )
• Genotype-steroidogenic phenotype relationships in patients with aldosteronomas and in experimental cell model systems (Applicant Lenders, Ph.D., Jacques W.M. )
• Hypoxia and MYC/MAX signaling pathways in chromaffin tumourigenesis (Applicant Eisenhofer, Ph.D., Graeme )
• Immune mechanisms and potential therapeutic interventions for sepsis-induced adrenal gland inflammation (Applicants Bornstein, Ph.D., Stefan R. ;  Kanczkowski, Waldemar ;  Zacharowski, Ph.D., Kai )
• Involvement of ALADIN in adrenal cell function and hormone and response (Applicant Hübner, Ph.D., Angela )
• Sonic hedgehog signalling in different forms of adrenal hyperplasia (Applicants Alexaki, Vasileia Ismini ;  Eaton, Suzanne )

• Spokesperson: Professor Stefan R. Bornstein, Ph.D.
• Leaders: Professor Dr. Triantafyllos Chavakis; Professor Graeme Eisenhofer, Ph.D.