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.
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.
|Finco, Isabella; Lerario, Antonio M; Hammer, Gary D (2018) Sonic Hedgehog and WNT Signaling Promote Adrenal Gland Regeneration in Male Mice. Endocrinology 159:579-596|
|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|
|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|
|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|
|Finco, Isabella; LaPensee, Christopher R; Krill, Kenneth T et al. (2015) Hedgehog signaling and steroidogenesis. Annu Rev Physiol 77:105-29|
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