ADD-SEX

The adrenal cortex is a central relay in health and disease that controls a multitude of physiological processes and is key in the body’s response to stress and infection. Control is achieved through a set of distinct steroid hormones that are released from highly specialised cells arranged in concentric zones. Our recent research has shown that the adrenal cortex undergoes surprisingly dynamic tissue renewal, which is fuelled by a complex set of progenitor cells and involves lineage conversion between different zones. Interestingly, adrenal tissue renewal, physiology and diseases are highly impacted by sex with many disorders occurring much more frequently in women than in men. Despite intensive research, the molecular underpinnings of adrenal biology, the mode of tissue homeostasis and the impact of sex remain poorly defined. The present research project will address these shortcomings: 1. Using single cell multiomics, spatial transcriptomics and epigenetic analysis we will delineate the cellular composition of the adrenal cortex, follow cellular differentiation in both sexes and integrate published and newly generated data in an easily accessible database. This atlas is expected to reveal the relationships between cell types found during development and adult adrenals and will represent an important resource for the scientific community. 2. We will exploit the above data to identify the molecular programs that underly stem cell recruitment, proliferation and differentiation. ChIP-Seq analysis for key transcription factors involved in zonation will be performed and the protein targets of the SUMOylation machinery identified. Functional analysis in mice will be carried out to test hypotheses obtained from the analysis of single cell and ChIP-Seq data. 3. By integrating single cell multiomics, spatial transcriptomics and ChIP-Seq data of sex hormone receptors from sophisticated genetic models, we will identify the molecular foundations of sex-specific differences in the adrenal cortex, evaluate sex hormone dependent and independent mechanisms and decipher the physiological reasons for these differences. We will also determine the influence of sex hormones on adrenocortical physiology and evaluate its impact on adrenal diseases. Taken together these studies are expected to have a far-reaching impact on the fields of endocrinology, physiology and stem cell research. Insights into adrenocortical stem cell biology may help us to develop novel therapeutic interventions aimed at activating stem cells in cases of adrenal insufficiencies or interfering with abnormal proliferation/secretion such as adenomas. By delineating sex specific pathways, we expect to gain insights into differences in adrenal physiology, the response to stress and identify the molecular reasons for sex bias of adrenal diseases. These insights are expected to develop novel or adjust existing treatments to better take into account a patient’s sex. While this research program focuses on the adrenal gland, many other organs show sexual differences and our study will serve as a paradigm for these systems. The success of this project will be assured by a consortium of three partners with complementary skill sets and genetic tools in developmental/stem cell biology, adrenal physiology and single cell analysis.