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. In this grant cycle our goal is to identify and characterize the cellular and geneti architecture of the adrenal capsular/cortical unit required to maintain the homeostatic integrity o the adrenal cortex in humans and mice. To this end our strategy and specific aims for this proposal are directed towards understanding how the adrenal capsular/cortical unit is established during embryonic life and maintained as an adult stem/progenitor cell niche. Based on our preliminary data, we hypothesize that the unique and differential regulation of the Sf1 gene in fetal and adult adrenocortical cells together with paracrine signaling of the capsular/cortical unit underlies this process. We propose to determine the mechanisms by which the fetal adrenal cortex participates in the establishment of the homeostatic stem/progenitor cell niche of the adult adrenal cortex (Aim 1);identify the genomic location and characterize the regulation of the enhancer of Sf1 that determines the identity of adult (definitive) adrenocortical cells (Aim 2);and define the paracrine and endocrine mechanisms by which the adrenal capsule and peripheral cortex coordinate adrenocortical regeneration (Aim 3). The studies proposed here will provide fundamental knowledge of adrenal organogenesis and organ maintenance and will lead to clinical insights into diseases of adrenal failure, providing th groundwork for novel therapeutic treatment of patients with intrinsic or iatrogenic adrenal insufficiency.

Public Health Relevance

Most hormone disorders of the adrenal gland occur in the context of organ failure or overgrowth. Using mouse models together with genomic approaches, we aim to characterize how the homeostatic stem cell/progenitor cell niche of the adrenal capsule and underlying cortex is established in the fetus and maintained in the adult. Such efforts are predicted to gain insights into diseases of adrenal failure and provide the groundwork for novel therapeutic treatment of patients with adrenal insufficiency.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK062027-11
Application #
8735932
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Basham, Kaitlin J; Hung, Holly A; Lerario, Antonio M et al. (2016) Mouse models of adrenocortical tumors. Mol Cell Endocrinol 421:82-97
Finco, Isabella; LaPensee, Christopher R; Krill, Kenneth T et al. (2015) Hedgehog signaling and steroidogenesis. Annu Rev Physiol 77:105-29
Xing, Yewei; Lerario, Antonio M; Rainey, William et al. (2015) Development of adrenal cortex zonation. Endocrinol Metab Clin North Am 44:243-74
Walczak, Elisabeth M; Hammer, Gary D (2015) Regulation of the adrenocortical stem cell niche: implications for disease. Nat Rev Endocrinol 11:14-28
Walczak, Elisabeth M; Kuick, Rork; Finco, Isabella et al. (2014) Wnt signaling inhibits adrenal steroidogenesis by cell-autonomous and non-cell-autonomous mechanisms. Mol Endocrinol 28:1471-86
Lerario, Antonio M; Moraitis, Andreas; Hammer, Gary D (2014) Genetics and epigenetics of adrenocortical tumors. Mol Cell Endocrinol 386:67-84
Krill, Kenneth T; Gurdziel, Katherine; Heaton, Joanne H et al. (2013) Dicer deficiency reveals microRNAs predicted to control gene expression in the developing adrenal cortex. Mol Endocrinol 27:754-68
Wood, Michelle A; Acharya, Asha; Finco, Isabella et al. (2013) Fetal adrenal capsular cells serve as progenitor cells for steroidogenic and stromal adrenocortical cell lineages in M. musculus. Development 140:4522-32
Heaton, Joanne H; Wood, Michelle A; Kim, Alex C et al. (2012) Progression to adrenocortical tumorigenesis in mice and humans through insulin-like growth factor 2 and β-catenin. Am J Pathol 181:1017-33
Kelly, Victoria R; Hammer, Gary D (2011) LRH-1 and Nanog regulate Dax1 transcription in mouse embryonic stem cells. Mol Cell Endocrinol 332:116-24

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