The adrenal cortex produces steroid hormones throughout postnatal life in response to stress and other physiological inputs. The endocrine cells of the cortex are constantly replenished, and the cortex remodels in response to prolonged changes in these inputs. While adrenocortical stem or progenitor populations that contribute to, and are regulated by, homeostatic and remodeling systems likely exist, the molecular identity of these cells, their location within the gland, and the intraadrenal signaling circuits that control their behavior are very poorly understood. The long-term goal is to understand the molecular and cellular logic that controls how the adrenal cortex is maintained and remodeled, an issue of interest from both basic and clinical scientific perspectives. The Sonic hedgehog (Shh) pathway was identified as a potential regulator of adrenal growth and remodeling, and a marker of adrenocortical progenitor and/or stem cell populations. Preliminary experiments led to the hypotheses that the Shh pathway plays critical roles in adrenocortical development, maintenance and remodeling, and identifies multiple adrenocortical progenitor and/or stem populations. These hypotheses will be tested in mouse models through three Aims. In the first Aim manipulations of Shh pathway activity in the adrenal cortex will test the hypotheses that Shh signaling plays multiple roles in the adrenal gland, including regulating capsule growth and maintenance, regulating steroidogenic cell differentiation and controlling a reciprocal signal produced by the capsule. In the second Aim murine genetic lineage tracing experiments will test the hypotheses that the adrenal cortical cells that make or receive the Shh signal have properties of progenitor or stem cells.
The third Aim will address the functional relationship between Shh pathway activity and gland remodeling using two experimental paradigms - dietary salt manipulation and chronic adrenocorticotropin or dexamethasone administration- to test the hypothesis that dynamic hedgehog signaling influences cortical remodeling and that physiological inputs regulate Shh pathway activity and modulate the fate of the progenitors identified by Shh signaling. Together these experiments will advance our understanding of adrenal biology by exploring novel molecular mechanisms that influence maintenance and remodeling of this important gland. They also will more broadly contribute to our understanding of the interface between signaling systems and animal physiology.

Public Health Relevance

The cortex, or outer region, of the adrenal gland produces steroid hormones throughout life;if hormone production is disrupted due to genetic mutation, as occurs in about 1:15000 people, it is lethal without lifelong daily hormone replacement therapy. This project will study the molecular mechanisms that maintain the cells in the adrenal cortex that produce steroids. Greater understanding of these mechanisms may lead to improved management of adrenal disorders and ultimately perhaps ways to treat patients by gene repair and cell replacement therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK081515-01A1
Application #
7730606
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Sato, Sheryl M
Project Start
2009-07-20
Project End
2014-06-30
Budget Start
2009-07-20
Budget End
2010-06-30
Support Year
1
Fiscal Year
2009
Total Cost
$384,720
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Guasti, Leonardo; Paul, Alex; Laufer, Ed et al. (2011) Localization of Sonic hedgehog secreting and receiving cells in the developing and adult rat adrenal cortex. Mol Cell Endocrinol 336:117-22
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King, Peter; Paul, Alex; Laufer, Ed (2009) Shh signaling regulates adrenocortical development and identifies progenitors of steroidogenic lineages. Proc Natl Acad Sci U S A 106:21185-90