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 goal during this grant cycle is to define the mechanisms by which the Shh- expressing progenitor cells are maintained during adrenal homeostasis. Based on our preliminary data, we hypothesize that the adrenocortical progenitor pool is maintained through a coordinated balance of both 1) the proliferative self-renewal of the undifferentiated Shh-expressing cells and 2) the differentiation of the Shh- expressing progenitor to the distinct steroidogenic cell types in adrenal cortex. To this end our strategy and specific aims for this proposal are designed to define 1) the intracellular mechanisms by which steroidogenic factor 1 (SF1) is activated during cell cycle to initiate unique transcriptional programs in the proliferating undifferentiated Shh-expressing progenitor cell, and 2) how extracellular signals, specifically the balance of paracrine (SHH/WNT4) and endocrine (circulating Angiotensin II) factors regulates progenitor cell fate under physiological conditions. The studies proposed here will provide fundamental knowledge of adrenal homeostatic maintenance and will provide the groundwork for future clinical insights and novel therapeutic treatments for patients with intrinsic or iatrogenic adrenal failure.
Most hormone disorders of the adrenal gland occur in the context of organ failure or overgrowth. Using both mouse and cell models, we aim to determine how adrenocortical progenitor homeostasis is maintained. Specifically, we will define endocrine/paracrine signals and intracellular mechanisms regulating the balance between adrenocortical progenitor proliferation versus differentiation. Such efforts are predicted to provide the groundwork for future clinical insights and novel therapeutic treatment for patients with adrenal insufficiency.
| 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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