The pituitary gland coordinates growth, fertility, metabolism and the stress response through release of hormones from small numbers of highly specialized cells. A delicate balance between cell division and differentiation, in part regulated by hormonal milieu, dictates pituitary gland size. There is a lack of understanding of the molecular pathways controlling progenitor cell behavior, and thus pituitary cell number, beyond embryogenesis. This gap in knowledge must be filled because pituitary diseases presenting with too few hormone producing cells (hypopituitarism) and too many cells (adenomas) represent a substantial health burden, with the prevalence of adenomas alone being 1 in 1,100. The long-term goal is to define the signaling pathways controlling proliferation of pituitary progenitor cels to understand the pathology behind hypopituitarism and pituitary tumors. The objective of this application is to determine the mechanism by which pituitary progenitor/stem cells are maintained in the postnatal and adult gland and the signals that control their expansion and differentiation. The central hypothesis is that Notch signaling in pituitary progenitors is necessary to maintain them in an undifferentiated state and to promote their proliferation in a context specific manner. Preliminary and published data from the applicant's lab support the proposed role of Notch signaling. The hypothesis that Notch is an integral component of pituitary progenitor cell behavior will be tested by pursuing three specific aims: 1) Determine the mechanism by which the balance between progenitor maintenance and differentiation is controlled during pituitary gland expansion after birth. 2) Determine the mechanism by which progenitor cells are maintained and mobilized in the adult pituitary gland. 3) Elucidate how endogenous hormone feedback loops can alter proliferation of pituitary cells. In each of these aims, proliferation and differentiation of pituitary progenitor cells will be assessed in vivo in te context of temporally controlled gain and loss of function of Notch signaling. Stem/progenitor cells in the postnatal and adult pituitary have only recently been described. This proposed research would advance the understanding of signaling pathways that integrate to control the activity of these progenitor cells. Based on the fact that therapies targeting Notch signaling are in early stage clinical trials for leukemia and breast cancer, there is the potential for the basic understanding of Notch action in pituitary progenitors to lead to treatment of pituitary tumors.

Public Health Relevance

Pituitary size anomalies, either hypoplasia or tumor growth, result in infertility, impaired stress response due to dysregulated cortisol secretion, and alterations in growth and metabolism. The proposed research will uncover the fundamental mechanism by which Notch signaling activity influences pituitary cell number, thus possibly identifying a point to intervene to increase or decrease cell number in the gland to reduce the associated morbidity and mortality with these common endocrine diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK076647-07
Application #
8703078
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Sato, Sheryl M
Project Start
2007-02-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
City
Champaign
State
IL
Country
United States
Zip Code
61820
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Biehl, Matthew J; Kaylan, Kerim B; Thompson, Robert J et al. (2018) Cellular fate decisions in the developing female anteroventral periventricular nucleus are regulated by canonical Notch signaling. Dev Biol 442:87-100
Hekman, Jessica P; Johnson, Jennifer L; Edwards, Whitney et al. (2018) Anterior Pituitary Transcriptome Suggests Differences in ACTH Release in Tame and Aggressive Foxes. G3 (Bethesda) 8:859-873
Biehl, Matthew Joseph; Raetzman, Lori Therese (2017) Developmental Origins of Hypothalamic Cells Controlling Reproduction. Semin Reprod Med 35:121-129
Eckstrum, Kirsten S; Weis, Karen E; Baur, Nicholas G et al. (2016) Icam5 Expression Exhibits Sex Differences in the Neonatal Pituitary and Is Regulated by Estradiol and Bisphenol A. Endocrinology 157:1408-20
Weis, Karen E; Raetzman, Lori T (2016) Isoliquiritigenin exhibits anti-proliferative properties in the pituitary independent of estrogen receptor function. Toxicol Appl Pharmacol 313:204-214
Kapali, Jyoti; Kabat, Brock E; Schmidt, Kelly L et al. (2016) Foxo1 Is Required for Normal Somatotrope Differentiation. Endocrinology 157:4351-4363
Edwards, Whitney; Nantie, Leah B; Raetzman, Lori T (2016) Identification of a novel progenitor cell marker, grainyhead-like 2 in the developing pituitary. Dev Dyn 245:1097-1106
Aujla, Paven K; Bogdanovic, Vedran; Naratadam, George T et al. (2015) Persistent expression of activated notch in the developing hypothalamus affects survival of pituitary progenitors and alters pituitary structure. Dev Dyn 244:921-34
Biehl, Matthew J; Raetzman, Lori T (2015) Rbpj-? mediated Notch signaling plays a critical role in development of hypothalamic Kisspeptin neurons. Dev Biol 406:235-46

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