PROPOSAL 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 strategy for this proposal is to focus on the role of SF1 and the SF1 target gene Dax1 in the regulation of adrenocortical growth maintenance. Based on our preliminary data, we hypothesize that unique transcriptional programs in subcapsular undifferentiated progenitor cells serve to maintain the functional capacity of the adrenal cortex.
Our specific aims are directed towards a systematic characterization of novel functions of SF1 critical to this process. We propose to determine the origin of the SF1 positive subcapsular cells (specific aim 1), define the role of Dax1 in the self-renewal and multipotent properties of these adrenocortical cells in vivo (specific aim 2) and determine the mechanisms by which SF1 is activated to initiate a unique proliferation-associated transcriptional profile in this subcapsular population (specific aim 3). The studies proposed here will provide the critical framework for understanding the role of SF1 in adrenocortical stem/progenitor cells in adrenal growth maintenance and lay the groundwork for future therapeutic efforts in diseases of adrenal growth including both hypoplasias and cancer.

Public Health Relevance

Most hormone disorders of the adrenal cortical occur in the context of organ failure or overgrowth. Increasing evidence indicates that the cortex constantly renews its cell population through the constant proliferation of uncommitted cells lying in and/or underneath the outer capsule. Using cellular systems, mouse models together with genomic approaches, we aim to characterize the stem/progenitor cells of the adrenal cortex and uncover the mechanisms by which these cells are regulated by SF1 in normal adrenal growth maintenance. Future efforts are predicted to focus on therapies that target this pathway and downstream genes that are found in the course of these studies to participate in adrenocortical stem/progenitor cell biology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062027-09
Application #
8217213
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
2002-07-01
Project End
2013-09-16
Budget Start
2012-02-01
Budget End
2013-09-16
Support Year
9
Fiscal Year
2012
Total Cost
$317,968
Indirect Cost
$97,445
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Xing, Yewei; Lerario, Antonio M; Rainey, William et al. (2015) Development of adrenal cortex zonation. Endocrinol Metab Clin North Am 44:243-74
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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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