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. In this grant cycle our goal is to identify and characterize the cellular and genetic architecture of the adrenal capsular/cortical unit required to maintain the homeostatic integrity of 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 the groundwork for novel therapeutic treatment of patients with intrinsic or iatrogenic adrenal insufficiency.
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.
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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|
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|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|
|Scheys, Joshua O; Heaton, Joanne H; Hammer, Gary D (2011) Evidence of adrenal failure in aging Dax1-deficient mice. Endocrinology 152:3430-9|
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|Wood, Michelle A; Hammer, Gary D (2011) Adrenocortical stem and progenitor cells: unifying model of two proposed origins. Mol Cell Endocrinol 336:206-12|
|Garcia-Perez, Jose L; Morell, Maria; Scheys, Joshua O et al. (2010) Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells. Nature 466:769-73|
|Looyenga, Brendan D; Wiater, Ezra; Vale, Wylie et al. (2010) Inhibin-A antagonizes TGFbeta2 signaling by down-regulating cell surface expression of the TGFbeta coreceptor betaglycan. Mol Endocrinol 24:608-20|
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