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)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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
2002-07-01
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
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
Lerario, Antonio Marcondes; Finco, Isabella; LaPensee, Christopher et al. (2017) Molecular Mechanisms of Stem/Progenitor Cell Maintenance in the Adrenal Cortex. Front Endocrinol (Lausanne) 8:52
Xing, Yewei; Morohashi, Ken-Ichirou; Ingraham, Holly A et al. (2017) Timing of adrenal regression controlled by synergistic interaction between Sf1 SUMOylation and Dax1. Development 144:3798-3807
Finco, Isabella; Lerario, Antonio M; Hammer, Gary D (2017) Sonic Hedgehog and WNT Signaling Promote Adrenal Gland Regeneration in Male Mice. Endocrinology :
Penny, Morgan K; Finco, Isabella; Hammer, Gary D (2017) Cell signaling pathways in the adrenal cortex: Links to stem/progenitor biology and neoplasia. Mol Cell Endocrinol 445:42-54
Nanba, Kazutaka; Chen, Andrew X; Omata, Kei et al. (2016) Molecular Heterogeneity in Aldosterone-Producing Adenomas. J Clin Endocrinol Metab 101:999-1007
Lee, Jiwon; Yang, Dong Joo; Lee, Syann et al. (2016) Nutritional conditions regulate transcriptional activity of SF-1 by controlling sumoylation and ubiquitination. Sci Rep 6:19143
Bornstein, Stefan R; Allolio, Bruno; Arlt, Wiebke et al. (2016) Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 101:364-89
Basham, Kaitlin J; Hung, Holly A; Lerario, Antonio M et al. (2016) Mouse models of adrenocortical tumors. Mol Cell Endocrinol 421:82-97
Nanba, Kazutaka; Omata, Kei; Tomlins, Scott A et al. (2016) Double adrenocortical adenomas harboring independent KCNJ5 and PRKACA somatic mutations. Eur J Endocrinol 175:K1-6
Xing, Yewei; Lerario, Antonio M; Rainey, William et al. (2015) Development of adrenal cortex zonation. Endocrinol Metab Clin North Am 44:243-74

Showing the most recent 10 out of 44 publications