Mechanisms of Adrenal Differentiation

ABSTRACT The long-range objective of our laboratory is to understand the cellular and molecular mechanisms by which signaling pathways and downstream transcription factors coordinate the specification of adrenocortical cells within the adrenal gland. Our goal during this grant cycle is to define mechanisms by which the transcription factor HHEX specifies identity and function of cells in the inner zona fasciculata (zF). Based on our preliminary data, we hypothesize that HHEX is a requisite factor for the enhanced glucocorticoid secretion during chronic stress adaptations; together with androgen-driven lipid catabolism and tissue renewal in the adrenal zF. To this end, our strategy and specific aims for this proposal are designed to 1) Define the intracellular mechanisms by which HHEX regulates the identity and function of the glucocorticoid-producing inner zF cells that are enriched during chronic stress (Abcb1b+ inner zF population), 2) Determine the contribution of HHEX to transcriptional programs the underly dynamic androgen-driven sterol flux in the adrenal zF and, 3) Characterize the role of HHEX in adrenal zF tissue renewal. The studies proposed here will provide fundamental knowledge of cellular heterogeneity in the adrenal cortex, specifically the cell populations producing glucocorticoids during stress adaptation, and will provide the groundwork for future clinical insights and therapeutic treatments for patients with chronic diseases of adrenal insufficiency and stress-related disorders.