Mechanisms Leading to Adrenal Zonation

Augusta University, Augusta GA

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Abstract

DESCRIPTION (provided by applicant): This application is being submitted in response to the NIH Notice: NOT-OD-09-058 NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. The parent application, "Mechanisms Leading to Adrenal Zonation", was last funded as an R01 grant through the NIDDK. Herein, we request funding to support a new specific aim that will allow us to extend our studies on adrenal zonation into transgenic mouse models. The human adrenal cortex can be divided into distinct zones that have both morphologic and biochemical differences. The production of aldosterone in the zona glomerulosa and cortisol in the zona fasciculata can be traced to the zone-specific expression of the enzymes involved in steroid biosynthesis. The mechanisms causing zonal expression of the steroidogenic enzymes have not been defined. In the parent R01 grant, we proposed to test the overall hypothesis that adrenal cell expression of steroidogenic enzymes results from the opposing activities of nuclear hormone receptors in the glomerulosa and fasciculata. Over the funding periods associated with this grant, we have made considerable progress in defining the molecular mechanisms controlling adrenal zonation but, by its nature, in vitro analyses require confirmation in vivo. Since the funding of this application, we have succeeded in selectively targeting the mouse adrenal glomerulosa using the Cyp11B2 promoter. This now provides the unique opportunity to expand the in vitro experiments of our past studies into the mouse adrenal. In this competitive supplement, we propose one Specific Aim that focuses on the development of a transgenic mouse that will allow the selective manipulation of adrenal glomerulosa genes. In the proposed studies this transgenic mouse will be used to determine the cell lineage leading to adrenal zonation. In summary, our recent successful targeting of the mouse adrenal glomerulosa has allowed us to propose a new Specific Aim that will: 1) greatly enhance the significance of the parent grant's proposed research, and 2) allow the development of a new mouse model that will act as a resource for many adrenal researchers. The funding of this revision will also act as an economic stimulus through the creation of a new graduate student position and spending on equipment, supplies and services needed to accomplish the research goals. PUBLIC HEALTH RELEVANCE: The proposed studies will lead to the development of a novel transgenic mouse model that will become an effective, indispensable tool to advance adrenal research. Herein, we will use this new mouse model to define the cell lineage for the zones of the adrenal cortex. Future studies will be able to use this model to better define the mechanisms leading to adrenal disease.