Benutzerspezifische Werkzeuge



Grant summary

Society faces an epidemic of stress-related disorders, ranging from cardiovascular and metabolic to inflammatory diseases that together comprise an overwhelming and rapidly growing burden to our health care systems. Obesity, diabetes, hypertension and mental disease stem from a toxic environment of inappropriate working conditions, over-nutrition and sedentary life style in an increasingly urbanized world. Both the UN and WHO have suggested strategies urging funding agencies to support research in this area. Surprisingly, the key stress organ of the human body involved in this emerging cluster of comorbidities, the adrenal gland, has not received due attention.

The adrenal gland produces steroids and catecholamines orchestrating basic metabolic, cardiovascular, neural and immune responses. This key regulatory function of the adrenal gland is based on a unique microenvironment integrating the two major endocrine stress systems: the steroid-producing adrenal cortex and the catecholamine-producing adrenal medulla. These systems provide substrate for intimate crosstalk with non-endocrine cells such as vascular endothelial cells, inflammatory cells and the recently discovered adrenal stem cells. The dense vascularisation and perfusion of the adrenal gland reflects the importance of the crosstalk between endocrine and non-endocrine cells within the adrenal microenvironment. Inflammation or tumourigenic processes of the adrenal gland may result in acute or chronic dysregulation of both adrenal and endocrine systems. Although it is well recognised that adrenal dysregulation is crucial in determining the outcome of stress-related diseases, little information exists about the underlying molecular mechanisms governing the fine regulation of the cellular crosstalk within the adrenal microenvironment.

Only a comprehensive understanding of the complex adrenal microenvironment, its responses and adaptation to external stimuli will allow us to unravel the alterations that form the basis of these stress-related disorders. Focusing on the adrenal with a comprehensive pathophysiological conceptual approach holds the promise for successful new diagnostic and therapeutic strategies. In particular, two major aspects of adrenal dysfunction will be addressed: (i) we will study mechanisms of adrenal hyperfunction in the context of adrenal hyperplasia and tumourigenesis, an aspect that bridges concepts of genes, development, stress and tumour formation with metabolic dysregulation; and (ii) we will study mechanisms of adrenal hypofunction due to genetic disorders, oxidative stress or in the context of inflammation, infection and sepsis. Relevant to the latter are mechanisms of regeneration whereby the unique adrenal microenvironment could provide the platform for therapeutic applications aimed at endocrine organ regeneration.

Understanding the mechanisms of adrenal hyperfunction or hypofunction in disease (e.g., adrenal dysfunction in inflammation or adrenal tumour formation) requires a thorough integrative approach involving the convergence of extra-adrenal and intra-adrenal signals and the detailed analysis of the interactions between endocrine and non-endocrine cells within the adrenal. We propose a systematic interdisciplinary study of the adrenal microenvironment ranging from specialised cellular systems to cell-specific genetically modified mice and translational mouse models to clinical applications involving analyses of human samples and multidisciplinary patient-oriented research protocols. The scientific components of this interdisciplinary study are well integrated with one another, thereby supporting a coordinated bidirectional bedside-to-bench and bench-to-bedside approach for successful translation of important scientific findings to improvements in clinical practice.

Our centre in Dresden unites a unique and complementary group of experts with high international visibility. We propose a cohesive programme bringing together a group of internationally established adrenal researchers supported by an interdisciplinary team of clinical chemists, immunologists, pharmacologists, vascular biologists, clinical endocrinologists and intensivists. This effort will help define the pathways of adrenal dysregulation in metabolic and inflammatory disease and the mechanisms of adrenal tumourigenesis. We anticipate that the collaboration of these research groups with efficient administration of resources (clinical data and biobanks, mouse models, cell culture systems, microarrays and facilities for state-of-the-art analytical work) will allow significant advancements in our understanding of the physiology and pathophysiology of the adrenal microenvironment. This in turn will provide the basis for better diagnostic tools and therapies for adrenal tumours or for adrenal hypofunction in stress-dependent inflammatory disorders. In addition, our work will pave the way for novel endocrine-adrenal-related regenerative therapies. This environment will foster ideal conditions for young researchers and physician-scientists to train in and perform cutting-edge basic and translational research on a highly relevant topic.